NZ312577A

NZ312577A - Use of optionally substituted n-(pyrrol-1-yl)-pyridinamines as anticonvulsant agents

Info

Publication number: NZ312577A
Application number: NZ312577A
Authority: NZ
Inventors: Francis Parker Huger; Sathapana Kongsamut; Craig Paul Smith; Lei Tang
Original assignee: Hoechst Marion Roussel Inc
Priority date: 1995-07-27
Filing date: 1996-07-08
Publication date: 1999-08-30
Also published as: NO980334D0; ATE218343T1; JP4189029B2; CA2225156C; MX9800774A; TW464497B; CN1191486A; CN1184969C; PT840609E; NO315148B1; AU6454796A; DK0840609T3; NO980334L; DE69621617T2; HK1015687A1; DE69621617D1; KR100445629B1; AR003471A1; JPH11510159A; ES2174081T3

Description

<div class="application article clearfix" id="description"> New Zealand No 312577 International No PCT/US96/11408 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates 27 07 1995, Complete Specification Filed 08 07 1996 Classification (6) A61K31/44 Publication date 30 August 1999 Journal No 1443 Title of Invention Use of unsubstituted and substituted n-(pyrrol-1-yDpyridinamines as anticonvulsant agents Name, address and nationality of applicant(s) as in international application form HOECHST MARION ROUSSEL, INC ,2110 East Galbraith Road, PO Box 156300, Cincinnati, Ohio 45215-6300, United States of America NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION WO 97/04777 PCT/US96/11408 USE OF UNSUBSTITUTED AND SUBSTITUTED N-fPYTmOL-1-YDPYRIDINAMINES AS ANTICONVULSANT AGENTS 10 BACKGROUND OF THE INVENTION Certain 2,3-dihydro-l-pyridinylamino)-indoles have been disclosed as having utility for the treatment of memory dysfunction characterized by cholinergic deficit as 15 well as anticonvulsant and analgesic utility (for example, see United States patents 5,179,099 and 5,296,488). In addition, certain N-(pyrrol-l-yl)pyridmamines, including certain compounds within the scope of the present invention, have been disclosed as having utility for 20 enhancing memory (for example, see United States patent 5,032,599) Furthermore, certain N- (pyridmyl) -lH-mdol-1-amines, including certain compounds within the scope of the present invention, have been disclosed as having utility for the treatment of obsessive compulsive disorders (for 25 example, see United States patent 5,3 56,910), for the enhancement of memory (for example, see United States patents 4,880,822 and 4,970,218), and as analgesic and antidepressant agents (for example, see United States patent 4,880,822) 30 -2- 7 •I O rr "? "7 , I * j SUMMARY OF INTENTION This invention relates to the use of a compound for the preparation of a pharmaceutical composition for the treatment of convulsions wherein the compound has the formula R2 15 wherein R is hydrogen, (Ci_-Cg) alkyl, (Co-Cq) alkenyl, (C2-10 Cg)alkynyl or phenyl (Cj_-Cg) alkyl, R- is hydrogen, halogen or (C^-Cg)alkyl, r2 is hydrogen, halogen or (Cj_-Cg) alkyl, or R- and R^ taken together witn the carbons to ^nich they are attacned form a benzene ring fused to the pyrrole ring vnerem the benzene ring is optionally substituted by one or two suostifcuents independently selected from the group of halogen, (C—Cg) alkyl, (Ci_-Cg) alko'cy, aryl (G>-Cg) alko.cy, hydroxy, nicro, ammo, (Ci~Cg > al-cylamino or di (C]_-Cg) alk/lammo, 20 ?3 15 hydrogen, r.alogen or (C--Cg ^ al <yl, F4 is Hydrogen, nalogen, aai.r.o or (Ci_-Cg) al'ol, n is 0 or 1, or a pnarr.aceuticail/ acceptable acid addition salt tr.ereof Described but not claimed is a method of treating a 25 patient m need of relief from convulsion which comprises administering to such a patient a convulsion-alleviating (followed by page 2a) J! I ;-'.3 JLCSLf-1 v r n » -2a- ^ 125 7 7.^ amount of a compound of the formula I (O)n wherein R is hydrogen, (C]_-Cg) alkyl, (C2-C5) alkenyl, (C2-Cg)alkynyl or pnenyl (O-Cg) alkyl, R^- is hydrogen, halogen or (C^-Cg) alkyl, R^ jls hydrogen, halogen or (Ci_-Cg) alkyl, or R- and R^ taken togetner wich tne carbons to waicn tney are attacned form a benzene ring fused to tne pyrrole ring wneram tne cer.rene ring 13 optionally substicared oy one or two substituents independently selected frcm tne group of halogen, (O-Cg) alcyl, (Ci_-Cg) alkcxy, aryl (Ci_-Cg) alko:cy, r.ycrc:o , nitro, amine, (C^-C5) alkylammo or di (C^-Cg ) al<ylam_r.o, P-1 is hydrogen, nalcger. or (C^. — — 5) al<-_/l, ?•* 13 nydrogen, nalcger., anmc cr (C—C5 al <yl, n is 0 or 1, cr a pnamacautically acceptable acid addition salt tnerecf (followed by page 3) -«JU ;:„>J n WO 97/04777 PCT/US96/11408 'wwne. Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo, optical, and geometrical isomers thereof where such isomers exist, as well as pharmaceutically acceptable acid 5 addition salts thereof and solvates thereof such as, for example, hydrates. The following general rules of terminology shall apply throughout the specification and the appended claims Unless otherwise stated or indicated, the term (Ci~ 10 Cg)alkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms Examples of (Ci-Cg)alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl 15 Unless otherwise stated or indicated, the term (C]_- Cg)alkoxy denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms. Examples of (C]_-Cg)alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, 20 t-butoxy and straight- and branched-cham pentoxy and hexoxy Unless otherwise stated or indicated, the term (C2~ Cg)alkenyl denotes a straight or branched alkenyl group having from 1 to 6 carbon atoms Examples of (C2~ 25 Cg)alkenyl include, for example, vinyl, allyl, 1-propenyl, 2-methyl-3-butenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl and the like Unless otherwise stated or indicated, the term (C2~ Cg)alkynyl denotes a straight or branched alkynyl group 30 having from 2 to 6 carbon atoms Examples of (C2- Cg)alkynyl include acetylenyl, propargyl, 1-propynyl, 2-methyl-3-butyny1, 3-methyl-1-butynyl, 2-methyl-2-butynyl and the like 10 -4- 3 1 2 B 7 7 - In a preferred situation the patient m need of relief from convulsion is treated with a compound of the formula R2 ^ tR3 *& I (0)n wherein R is hydrogen, (Ci-Cg)alkyl, (C2-C5)alkenyl, (C2-Cg)alkynyl or phenyl(Ci_-Cg)alkyl, R- is hydrogen, halogen or (Ci_-Cg) alkyl, R2 is hydrogen, halogen or (Ci_-Cg) alkyl, R3 is hydrogen, halogen or (C^-Cg)alkyl, R- is hydrogen, halogen, ammo or (C]_-Cg) alkyl, n is 0 or 1, or a pnarmaceutically acceptaole acid addition salt t.iereof Preferably P2 and R3 are nydrogen, R^ is hydrogen or (Ci~Cg)alkyl and n is 0 In anotner preferred situation tne patient m need of relief from convulsion is treated with a ccmoound of cne formula :o I .j ] n r c r i w ,, 312577.1 (0)n wherein R is hydrogen, (Ci-Cg)alkyl, (C2~Cg)alkenyl, (C2-Cg)alkynyl or phenyl(C^-Cg)alkyl, R3 2.s hydrogen, halogen, (Cj-Cg) alkyl or (CH2) zMH2' R4 is hydrogen, halogen, amino or (C^-Cg)alkyl, X is hydrogen, halogen, (C^-Cg)alkyl, (C^-Cg)alkoxy, aryl (C^-Cg)alkoxy, hydroxy, nitro, amino, (C^-Cg)alkylamino or di (C^-Cg)alkylamino, m is 1 or 2, n is 0 or 1; and 2 is 1 or 2, or a pharmaceutically acceptable acid addition salt thereof Preferably X is hydrogen, F3 is hydrogen or methyl, R4 is hydrogen or fluoro and n is 0 The compounds of Formula I used in the methods can be prepared by utilizing the synthetic scheme described below where the parameters R, R-, R^, R3, r4( x, m, n and z nave the respective meanings as defined above unless otherwise indicated WO 97/04777 -6- PCT/US96/11408 STEP A An N-ammopyrrole of Formula II as allowed to react with a chloro- or fluoropyndme of Formula III (where X as chlorane or fluorine) to afford a compound of Formula la R2 -}-R3 Rl^" ^IM— An (II) R4-f — X- (0)n (III) R2V-n n-R3 R4—)- (0)n NT r^-R (I) The reaction is typically carried out m an organic solvent such as bis(2-methoxy-ethyl)ether, diethyl ether, dimethyl ether, dioxane, tetrahydrofuran dimethylformamide, 10 dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoramide, dimethylsulfoxide, ethanol, isopropanol and the like at a temperature of between about 20°C and 150°C STEP B 15 As an alternative to STEP A, a compound of Formula lb obtained above is allowed to react with a strong base such as sodium hydride or potassium hydride in a suitable solvent such as a polar aprotic solvent including, for 20 example, dimethylformamide, dimethylsulfoxide and ethereal solvents or an aromatic hydrocarbon at a temperature of between about -10°C and 50°C, preferably between about 0°C and -25°C to form the corresponding nitrogen anion and the latter is allowed to react with a loweralkyl chloride or 25 bromide of the formula R-Hal (where Hal is chlorine or bromide and R is loweralkyl) or a diloweralkyl sulfate of the formula (RO)2SC>2 at a temperature of between about - WO 97/04777 -7- PCT/US96/11408 10°C and 80°C, preferably between 0°C and 25°C, to afford the compound of Formula la where R is loweralkyl R2 -j-R3 1}Na^ la 2)R-Hal R=Loweralkyi (0)n (lb) 10 15 STEP C As an alternative to STEP A, when R3 is hydrogen or (C1-C5)alkyl and R^ and R2 are hydrogen, (C^-Cg)alkyl or halogen, compound I can be obtained by reacting a compound of Formulcx IV with a compound of Formula V R1 or R2-H3CO/ - -4R3 + (IV) The reaction is typically conducted m an alkanoic acid, preferably lower alkanoic acid such as, for example, glacial acetic acid, propanoic acid or formic acid at a temperature of from about 80° to about 120°C STEP D Where and R^ taken together with the carbons to which they are attached form a benzene ring fused to the pyrrole ring to form a compound of Formula VI WO 97/04777 -8- PCT/US96/11408 (X)m-j- 4-R3 ^Sr D, if^'Sl R4- (0)n (VI) where X is ammo, (C2-C5)alkylamino or da (C]_-Cg) alkylamino, a compound obtained from STEP A or STEP B having the appropriate substituents except for X and X is nitro, is converted to the ammo or alkylamino group using reduction methods known m the art STEP E Where compounds of Formula VI where X is hydroxy are 10 desired, a compound obtained from STEP A or STEP B having the appropriate substituents except for X and X is benzyloxy, is converted to the corresponding hydroxy compound m a routine manner known m the art 15 STEP F Where compounds of Formula I where R4 is ammo are desired, a compound obtained from STEP A or STEP B having the appropriate substituents except for R4and R4 is nitro is converted to the corresponding amino compound m a manner 20 known m the art STEP G Where compounds of Formula I where the nitrogen is m the 3-position of the pyridine ring and R4 is hydrogen are 25 desired, a compound obtained from STEP A or STEP B having the appropriate substituents except for R4 and R4 is halogen substituted at the 5-position of the pyridine ring is WO 97/04777 -9- rCT/US%/I140S converted to the corresponding compound where R* is hydrogen m a manner known m the art Compounds I of the instant invention are useful as anticonvulsant agents due to their anticonvulsant activity 5 m mammals. Anticonvulsant potential is measured by inhibition of t^H]batrachotoxin binding in vitro. and anticonvulsant activity is measured using the Supramaximal Electroshock Test m the male mouse 10 INHIBITION OF f^HlBATRACHOTOXIN (BTX) BINDING TO BRAIN MEMBRANE SODIUM CHANNELS PURPOSE: This assay was established to determine the direct 15 effect of test compounds on the binding of [3h]batrachotoxin to sodium channels m a membrane preparation from rat brain It has been shown that the alkaloid batrachotoxin binds to a unique site (site II) of the neuronal membrane sodium channel to activate the 20 voltage-sensitive sodium channel (Catterall, 1980) Furthermore, it is now known that certain anticonvulsant agents, such as diphenylhydantom and carbamazepme, allosterically inhibit the binding of [3H]batrachotoxin to membrane sodium channels (Willow and Catterall, 1982, 25 Olsen, 1986) METHODS Vesicular preparations of male Wistar rat cortices were used for the binding assay Briefly, the rat brain 30 was removed and the cortex was separated and placed m a glass homogenizer filled with 2 ml ice-cold Krebs buffer The tissue was homogenized at 3,500 rpm for 6 up and down strokes, and centrifaged at 1,000 g for 15 minutes The supernatant was discarded and the pellet was resuspended m Wo 97/04777 PC7/US96/11408 binding medium (130 mM choline chloride, 5.5 mM glucose, 0 8 mM MgSC>4, 5 4 mM KCl and 50 mM HEPES, pH 7.4) . Incubations were carried out m a total volume of 25 0 pi containing 1 pM tetrodotoxin, 0 02 mg of scorpion venom, 25 5 nM [3H]batrachotoxin, approximately 400 pg of protein of the vesicular preparation and various concentrations of the test compound After 60 minutes incubation at 25°C, the reaction was terminated by diluting with 3 ml of wash medium (163 mM choline chloride, 1 8 mM CaCl2< 0 8 mM MgSC>4 10 and 5 mM HEPES, pH 7 4) and collecting under vacuum on a glass-fiber filter The filters were then washed twice with 3 ml of wash medium and placed m scintillation vials with 5 ml of Esocmt (National Diagnostics) The tritium content was measured by scintillation spectroscopy Non- 15 specific binding of [3h]batrachotoxin was determined m the presence of 3 00 pM vetratndme and was determined to be 4 75±0 15% of the total binding. DRUGS 20 Drugs were dissolved in 50 mM HEPES buffer, pH 7.4, or dissolved m ethanol and diluted in 50 mM HEPES buffer, pH 7 4 REFERENCES 25 1 Catterall, W.A. (1980) Neurotoxins that act on voltage-sensitive sodium channels m excitable membranes Ann Rev. Pharmacol. Toxicol 20, 15-43 2 Willow, M. and Catterall, W A (1982) Inhibition of 30 binding of [3H]batrachotoxmin A 20- -benzoate to sodium channels by the anticonvulsant drugs diphenylhydantoin and carbamazepme Mol Pharmacol 22, 627-635 WO 97/04777 -11- PCI7US96/11408 3 Olsen, R W (19 86): Comrulsant and anticonvulsant drug receptor binding, In* Receptor Binding m Drug Research (R.A. O'Brien, ed.) Marcel Dekker, New York, 1986, pp 93-123. 5 TABLE I Inhibition of [3H]Batrachotoxin Binding COMPOUND IC50 (UM) N- (n-Propyl) -N- (4-pyridmyl) -lH-mdol-l-amme HCl 5 N- (3-f luoro-4-pyridmyl) -3-methyl-N-propy1-1H-indo1-1-amine HCl [also known as N-(n-Propyl)-N-(3-fluoro-4-pyridmyl) -lH-3-methylmdol-1-amme HCl] 31 (Reference Compound) 94 Carbamazepme N- (4-pyridmyl) -lH-indol-1-amine 18 N-(1-methylethyl)-N-(4-pyridmyl) -lH-mdol-l-amme 9 N- (2-methylpropyl) -N- (4-pyridmyl) -lH-indol-1-amine 9 5-bromo-N- (4-pyridmyl) -1H-indol-1-amine 23 5-bromo-N-propyl-N-(4-pyridmyl) -lH-mdol-l-amme 14 N- (3-chloro-4-pyridmyl) -1H-mdol-l-amme 14 N- (3-chloro-4 -pyridmyl) -N-propy 1 - 1H - mdol -1 - amine 32 4- [N- {IH-mdol-l-yl) ]-3,4-pyridmamme 22 N- (3-methyl-4-pyridmyl) -1H-mdol-l-amme 21 3 -chloro-N- (4 -pyridmyl) -1H-mdol-1-amine 11 3-chloro-N-propyl-N-(4-pyridmyl) -lH-mdol-l-amme 10 3-methyl-N- (4-pyridmyl) -1H-mdol-1-amine 11 3-ethyl-N-methyl-N-(4-pyridmyl) -lH-mdol-l-amme 12 3-aminomethyl-N-propyl-N-(4-pyridmyl) -lH-mdol-l-amine 10 WO 97/04777 -12- PCT/US96/11408 3-ammoethyl-N- (4-pyridmyl) -lH-mdol-l-aiuine 44 1-[propyl-4-(3-f luoropyridmyl) amino] -1H-indol-5-ol 70 3-methyl-l-(4- pyridmylamino) -lH-mdol-5-ol 20 3-methyl-l-(propyl-4-pyridmyl ammo) -lH-mdol-5-ol 21 N- (3-chloro-4-pyridmyl) -3 -me thy 1 - 1H - mdo 1 -1 - amine 29 N- (3-chloro-4-pyridmyl) -3 -methyl-N-propyl-lH-mdol-1-amine 44 N- (3-f luoro-4-pyridmyl) -3-me t hyl -1H - mdo 1 -1 - ami ne 42 3-methyl-l-[propyl-(3-fluoro- 4-pyridmyl) ammo] -lH-mdol- 5-ol 19 N- (3-pyridmyl) -lH-mdol-1-amme 12 N- (2-pyridmyl) -lH-mdol-1-amine 12 N- (lH-pyrrol-l-yl)-4-pyridmamine 40 N-ethyl-N-(lH-pyrrol-l-yl)-4-pyridmamme 86 N-propyl-N-(lR-pyrrol-lyl)-4-pyridmamme 66 3-fluoro-N-propyl-N-(1H-pyrrol-lyl) -4-pyridmamme 46 SUPRAMAXIMAL ELECTROSHOCK IN MICE PURPOSE 5 This procedure is used as to predict anticonvulsant activity of a test compound m vivo by its ability to block a full tonic seizure induced by a supramaximal electroshock stimulation as an indication of efficacy in preventing grand mal seizures 0 METHODS Male CD-I mice (Charles River) weighing 18-30 grams were housed m accordance with the "NIH Guide to Care and Use of Laboratory Animals" (National Institutes of Health WO 97/04777 -13- PCT/US96/11408 Care Publication 85-23, revised 1985) with a 12 hour light/dark cycle and free access to food and water On the day of testing, animals are brought to the laboratory and randomly assigned to groups of six for the time course 5 experiments and to test groups of ten for the dose-response experiments. The apparatus used for the test was the Wahlquist Electroshock Stimulator (Model H), which has a power source of 120 volts ac. A current of 15 5 mA lasting for 300 msec 10 was delivered by placing the terminals of the stimulator across the eyes of the animal This stimulus results m a tonic seizure, defined as a brief period of hmdlimb flexion followed by a prolonged period of hmdlimb extension A compound is considered to give protection if 15 the mouse does not exhibit extensor tonus, which can be defined as the hmdlimb extension portion of the seizure. Protection is calculated as a normalized percent inhibition relative to a vehicle treated control group A time course is performed to determine the peak time 20 of drug action and then a dose response performed at the peak time to determine drug potency Mice are dosed m a randomized fashion using a total of 4 dose groups and one vehicle control group The ED50 value and 95% confidence limits are calculated by a computerized Litchfield and 25 Wilcoxon analysis DRUGS Drugs are prepared dissolved in distilled water and, if insoluble a drop of surfactant is added Drugs are 30 routinely administered mtraperitoneally for this test and given m a dosage volume of 10 ml/kg. REFERENCES 1 Woodbury, L A and Davenport, V.P (1952)- Design and 35 use of a new electroshock seizure apparatus and analysis of WO 97/04777 -14- PCT/US96/11408 factors altering seizure threshold and pattern Arch Int Pharmacodyn 92, 97-107 TABLE II INHIBITION OP SUPRAMAXIMAL ELECTROSHOCK IN MICE COMPOUND ED50 (mg/kg) N- (n-Propyl) -N- (4-pyridmyl) -lH-mdol-l-amine HCl 14 2 N- (3-Fluoro-4-pyridmyl) -1H-3-methyl-N- (n-propyl) -mdol-1-amme HCl [also known as N-(n-Propyl)-N-(3-fluoro-4-pyridmyl) -lH-3-Tnethylmdol-1-amme HCl] 50% @ 3 0 and 60 mpk 3-Methyl-N- (4-pyridmyl) -1H-mdol-l-amine oxalate [also known as N- (4 -pyridmyl) - 1H-3 -methyl mdol-1 -amine oxalate] 13 3-Methyl-N-propyl-N-(4-pyridmyl) -lH-mdol-l-amme maleate [also known as N-(n-Propyl) -N- (4-pyridmyl) -1H-3-methylmdol-1-amine maleate] 14 4 N-(2 5-Dimethyl-lH-pyrrol-l-yl)-N-(n-propyl)-4-pyridmamme Maleate 50 1 (Reference Compounds) Diphenylhydantom 9 4 Carbamaz epme 18 6 -15- -312577.1 Effective quantities of the compounds of this invention may be administered to a patient by any of the various methods, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or 5 suspensions, and m some cases intravenously in the form of sterile solutions. The free base final products, while effective themselves, may be formulated and administered m the form of their pharmaceutically acceptable acid addition salts for purposes of stability, convenience of 10 crystallization, increased solubility and the like. Acids useful for preparing the pharmaceutically acceptable acid addition salts of the invention include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as well 15 as organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric and oxalic acids The active compounds useful in the present invention may be orally administered, for example, with an inert diluent or with an edible carrier, or they may be enclosed m gelatin 20 capsules or they may be compressed into tablets For the purpose of oral therapeutic administration, the active compounds of the invention may be incorporated with excipients and used m the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum 25 and the like These preparations should contain at least 0 5% of active compounds, but may be varied depending upon the particular form and may conveniently be between 4% to aoout 70% of the weight of the unit The amount of active compound in such composition is such that a suitable dosage 30 will oe oDtamed Preferred compositions and preparations according to tne present invention are prepared so that an oral dosage unit form contains between 1 0-300 milligrams of active compound The tablets, pills, capsules, troches and the like may 35 also contain the following ingredients a binder such as 3 -16- 3 1 2 5 7 7 . ^ micro-crystalline cellulose, gum tragacanth or gelatin, an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, cornstarch and the like, a lubricant such as magnesium stearate or Sterotex, a glidant 5 such as colloidal silicon dioxide, and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring When the dosage unit form in capsule, it may contain, in addition to material of the above type, a 10 liquid carrier such as a fatty oil Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings Thus, tablets or pills may be coated with sugar, shellac or other enteric coating agents A syrup may contain, m 15 addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, coloring and flavors Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used 20 For the purpose of parenteral therapeutic administration, the active compounds may be incorporated into a solution or suspension These preparations should contain at least 0 1% of active compound, but may be varied between 0 5 and about 3 0% of 25 the weight thereof The amount of active compound in such compositions is such that a suitable dosage will be obtained Preferred compositions and preparations according to tne present inventions are prepared so that a parenteral dosage unit contains between 5-3 00 milligrams of 30 active compound The solutions or suspensions may also include the following components a sterile diluent such as water for injection, saline solution, fixed oils, polyetnylene glycols, glycerine, propylene glycol or other synthetic 35 solvents, antibacterial agents such as benzyl alcohol or J'- J u J n r , -it,-- WO 97/04777 -17- PCT/US96/11408 methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediammetetraacetic acid, buffers such as acetates, citrates or phosphates and agents for the adjustment of 5 tonicity such as sodium chloride or dextrose. The parental preparations can be enclosed m disposable syringes or multiple dose vials made of glass or plastic Examples of the compounds of this invention include N- (lH-Pyrrol-l-yl) -4-pyridinamme 10 N-Methyl-N- (lH-pyrrol-l-yl) -4-pyndinairune N-Ethyl-N- (lH-pyrrol-l-yl) -4-pyridinamme N-Propyl-N- (lH-pyrrol-l-yl) -4-pyridinamme N-Phenylmethyl-N-(lH-pyrrol-l-yl)-4-pyridinamme N- (Butyl) -N- (lH-pyrrol-l-yl) -4-pyridinamme 15 N- (2-Propenyl) -N- (lH-pyrrol-l-yl) -4-pyridmamine N- (2-Propynyl) -N- (lH-pyrrol-l-yl) -4-pyridinamme N-(2-Chloro-lH-pyrrol-l-yl)-N-methyl-4-pyridinamme N-(2-Chloro-lH-pyrrol-l-yl)-N-ethyl-4-pyridmamine N- (2-Chloro-lH-pyrrol-l-yl) -N-propyl-4-pyndmamine 20 N- (2-Chloro-lH-pyrrol-l-yl) -4-pyridmamine 2-Butyl-N-methyl-N-(lH-pyrrol-l-yl)-4-pyridmamine N-(2-Ethyl-lH-pyrrol-l-yl)-N-methyl-4-pyridinamine N-Methyl-N- (2-propyl-lH-pyrrol-l-yl) -4-pyridmamme N- (4-Pyridinyl) -lH-indol-l-amme 25 N-Methyl-N- (4-pyridmyl) -lH-indol-l-amme N-Ethyl-N- (4-pyridinyl) -lH-mdol-l-amme N-Propyl-N- (4-pyridmyl) -lH-mdol-l-amine 5-Methoxy-N-propyl-N- (4-pyridmyl) -lH-mdol-l-amine 3-Ethenyl-N-methyl-N- (4-pyridmyl) -lH-mdol-l-amme 30 3-Ethyl-N-methyl-N- (4-pyridmyl) -lH-mdol-l-amine 5-Chloro-N- (4-pyridmyl) -lH-mdol-l-amine 5-Chloro-N-propyl-N- (4-pyridmyl) -lH-mdol-l-amine 5-Bromo-N- (4-pyridmyl) -lH-indol-l-amme 5-Bromo-N-methyl-N- (4-Pyridmyl) -lH-mdol-l-amine 35 5-Bromo-N-propyl-N- (4-pyridinyl) -lH-mdol-l-amme WO 97/04777 -18- PCT/US96/11408 5-Nitro-N-(4-pyridinyl)-lH-mdol-l-amme N-Methyl-5-nitro-N- (4-pyrxdinyl) -lH-mdol-l-amine 3-Methyl-N-(4-pyridmyl)-lH-xndol-1-amine 3-Methyl-N-propyl-N-(4-pyridmyl)-IH-xndol-l-amxne N-(3-Fluoro-4-pyndmyl)-3-methyl-lH-xndol-1-amine N- (3-Fluoro-4-pyrxdmyl) -3-methyl-N-propyl-lH-indol-l-amme N- (3-Fluoro-4-pyridmyl) -N-propyl-lH-mdol-1-amine 2-Methyl-N- (4-pyridmyl) -lH-mdol-l-amme N- (3-Methyl-4-pyridmyl) -lH-indol-1-amine N- (3-Methyl-4-pyridmyl) -N-propyl-lH-mdol-l-amme N- (3-Fluoro-4-pyridmyl-IH-mdol-l-amine N- (3-Chloro-4-pyridmyl) -lH-mdol-l-amme N- (3- (Fluoro-4-pyridmyl) -2-methyl-lH-mdol-l-amme N- (3-Chloro-4-pyrxdinyl) -3-methyl-lH-mdol-l-amme N-Propyl-N- (4-pyridmyl) -3-ethenyl-lH-mdol-l-amme 3-Ethyl-N-propyl-N- (4-pyridinyl) - lH-mdol-l-amme N-Butyl-N- (4-pyridmyl-IH-mdol-l-amine N- (2-Propynyl) -N- (4-pyridmyl) -lH-mdol-l-amme N-(2-Methylpropyl)-N-(4-pyridmyl)-1H-indol-1-amine N-Pentyl-N- (4-pyridmyl) -lH-indol-l-amine N- (1-Methylpropyl) -N- (4-pyridmyl) -lH-mdol-l-amine N- (1-Methylethyl)-N- (4-pyridmyl) - lH-mdol-l-amme 2-Methyl-N-propyl-N- (4-pyridinyl) -lH-mdol-l-amine N- (3 -Fluoro-4-pyridmyl) -N- (2-propenyl) -3-methyl-lH-mdol-1-amme N- (3 -Chloro-4-pyridmyl) -N-propyl-lH-mdol-l-amme N- (3-Fluoro-4-pyridmyl) -N- (2-propynyl) -lH-mdol-l-amme N- (3-Fluoro-4-pyridmyl) -3-methyl-N- (2-propynyl) -lH-mdol-1-amme N- (3-Fluoro-4-pyridmyl) -2-methyl-N-propyl-IH-mdol-l-amine N-(3-Cnloro-4-pyridmyl)-3-methyl-N-propyl-lH-indol-l-amine N- (3-Fluoro-4-pyridmyl) -N- (2-propenyl) -lH-mdol-l-amme 4- [N- (IH-indol-l-yl) ] -3 , 4-pyridmamme, 3-chloro-N- (4-pyridmyl) -lH-mdol-l-amine, 3 -chloro-N-propyl-N- (4-pyridmyl) -lH-indol-l-amme, WO 97/04777 -19- PCT/US96/11408 3-ammomethyl-N-propyl-N- (4-pyridmyl) -lH-a.nd0l-l-aro2.ne, 3-aminoethyl-N- (4-pyridmyl) -lH-mdol-l-amme, 1-[propyl-4-(3-fluoropyndmyl) ammo]-lH-indol-5-ol, 3-methyl-l- (4-pyridinylammo) -lH-indol-5-ol, 5 3-methyl-l- (propyl-4-pyridanylamino) -lH-mdol-5-ol, 3-methyl-l- [propyl- (3-f luoro-4-pyridmyl) ammo] -lH-mdol-5-ol, N- (3-pyridmyl) -lH-indol-1-amine, N- (2-pyridmyl) -lH-mdol-l-amme, 10 N-(2,5-dimethyl-lH-pyrrol-l-yl)-N-(n-propyl)-4-pyridmamme, or 3-fluoro-N-propyl-N-(lH-pyrrol-l-yl)-4-pyridinamine. The following examples are presented m order to 15 illustrate the synthesis of various compounds which can be used for the method of this invention EXAMPLE 1 U I NH X 20 N- (lH-Pvrrol-l-vl) -4-pvridmamine A solution of 4-chloropyridme (15 g) and N-aminopyrrole (18 g) m 225 ml of diglyme was stirred at 150°C for one hour and thereafter cooled, diluted with water and basified with sodium carbonate The mixture was 25 extracted with ethyl acetate, and the organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated to an oil This oil was purified by high performance liquid chromatography (HPLC hereafter) using silica gel and ethyl acetate to give 12 g of a solid, m.p WO 97704777 -20- PCT/US96/11408 150°C Five grams of the solid was recrystallized twice from benzene to give 2.8 g of crystals, m p 153-154°C. ANALYSIS 5 Calculated for C9H9N3 67.90%C 5 70%H 26 40%N Found: 67.53%C 5 81%H 26 18%N EXAMPLE 2 Nr I N CH3 o hr N-Methyl-N-(lH-pvrrol-l-vl)-4-pvridmamine hydrochloride To an ice-cooled suspension containing 1 5 g of sodium hydride m 5 ml of dimethylformamide was slowly dropped a 15 solution of N- (lH-pyrrol-l-yl) -4-pyridmamme (4 g) in 10 ml of dimethylformamide After the initial brisk hydrogen evolution subsided, the reaction mixture was slowly warmed to ambient temperature and thereafter warmed at 50°C for thirty minutes The reaction mixture was again cooled with 20 an ice bath and a solution of dimethyl sulfate (3 8 g) in 5 ml of dimethylformamide was slowly added After thirty minutes, the reaction mixture was stirred with 3 00 ml of ice water and extracted with dichlorornethane The organic extract was washed with water 25 and saturated sodium chloride solution and thereafter dried over anhydrous magnesium sulfate, filtered and evaporated to 4 g of an oil This oil was purified by HPLC (silica gel, ethyl acetate) to give 3 5 g of an oil This oil was dissolved m 10 ml of warm isopropanol and filtered, and WO 97/04777 -21- PCT/US96/11408 thereafter converted to the hydrochloride salt by the addition of ethereal hydrogen chloride The crystals which formed upon cooling were collected and dried to give 3 1 g of crystals, m p. 226-227°C These crystals were sublimed at 135-150°C @ 0.01 mm Hg to give 2.9 g of crystals, m.p 226-227°C. ANALYSIS: Ca3 culated for C10H11N3-HCl 57 .28%C 5 77%H 20.04%N Found 57.39%C 5 78%H 19.99%N N-Ethvl-N-flH-Pvrrol-l-vl)-4-pvridmamine hydrochloride A solution of N- (lH-pyrrol-l-yl) -4-pyridmamme (4 g) in 20 ml of dimethylformamide was slowly added dropwise to an ice-cooled suspension containing 1.2 g of sodium hydride m 5 ml of dimethylformamide After the initial brisk reaction subsided, the mixture was stirred cold for thirty minutes, and thereafter a solution of diethyl sulfate (4.3 g) in 10 ml of dimethylformamide was added. After stirring twenty hours at ambient temperature, the reaction mixture was quenched with 500 ml of water and extracted with dichloromethane The organic extract was washed with water and saturated sodium chloride solution and thereafter dried over anhydrous magnesium sulfate, filtered and evaporated to 4 3 g of an oil This oil was purified by HPLC (silica, ethyl acetate) to give 3.7 g of an oil This oil was dissolved m 10 ml of warm isopropanol, filtered, and EXAMPLE 3 WO 97/04777 -22- PCT/US96/11408 acidified by the addition of ethereal hydrogen chloride The product which formed upon cooling was collected and dried to give 3 3 g of a solid, m p 224-225°C. ANALYSIS. 5 Calculated for CnHi3N3»HCl 59 06%C 6.31%H 18 79%N Found: 58 84%C 6.52%H 18 61%N EXAMPLE 4 n jr 10 N-Propvl-N-flH-pvrrol-l-vl)-4-pyridinamine hydrochloride A solution of N-(lH-pyrrol-l-yl)-4-pyridmamine (3 g) m 25 ml of dimethylformamide was slowly dropped into a suspension containing 1 g of sodium hydride m 5 ml of dimethylformamide After the anion formation, the 15 reaction mixture was cooled with an ice bath and a solution of 1-bromopropane (2 8 g) in 5 ml of dimethylformamide was slowly added After stirring one hour, the reaction mixture was quenched with water and extracted with dichloromethane The organic extract was washed with water 20 and saturated sodium chloride solution, and thereafter dried over anhydrous magnesium sulfate, filtered and evaporated to an oil This oil was purified by flash chromatography (silica, ethyl acetate) to give 5 g of an oil This oil was converted to the hydrochloride salt m 25 warm isopropanol The crystals which formed upon dilution with ether were collected and dried to give 3 3 g of a solid, m.p 230°C-232°C (dec ) This material was recrystallized from isopropanol-ether to give 2 6 g of crystals, m p 232-233°C (decomposition, hereafter "dec ") WO 97/04777 -23- PCT/US96/11408 ANALYSIS. Calculated for C12H15N3*HC1 60 62%C 6.78%H 17 68%N Found. 60 70%C 6.88%H 17 67%N EXAMPLF 5 isr XT N-Phenvlmethvl-N- (IH-Pvrrol-l-vl) -4-pvndinamine hydrochloride A solution of N- (IH-pyrrol-l-yl) -4-pyridmamme (4 g) 10 m 20 ml of dimethylformamide was slowly added to an ice-cooled stirred suspension containing 1.1 g of sodium hydride in 5 ml of dimethylformamide After the anion formation, a solution of benzylbromide (4 7 g) m 10 ml of dimethyl formamide was slowly added After stirring thirty 15 minutes, the reaction mixture was stirred with 500 ml of ice water and extracted with ether The organic extract was washed with water and saturated sodium chloride solution thereafter and dried over anhydrous magnesium sulfate, filtered and evaporated to 6 g of an oil This 20 material was purified by flash chromatography (silica, ethyl acetate) to give 4 4 g of the product as a solid, m p 77-79°C This material was converted to the hydrochloride salt m 2 0 ml of warm ethanol by the addition of ethereal hydrogen chloride The crystals which formed 25 upon cooling and dilution with ether were collected and dried to give 3.1 g of white crystals, m p 210-211°C ANALYSIS- Calculated for C16H15N3.HC1 67 24%C 5 64%H 14 71%N WO 97/04777 -24- PCT/US96/11408 Found 67 15%C 5 67%H 14 76%N EXAMPLE 6 N-(Butvl)-N-(lH-Pvrrol-l-vl)-4-pvridinamme hydrochloride A solution of N- (lH-pyrrol-l-yl) -4-pyridmamine (4 g) m 20 ml of dimethylformamide was slowly added to an ice-cooled suspension of sodium hydride (60% oil dispersion, 1 1 g) m 5 ml of dimethylformamide After the anion formation, a solution of 1-bromobutane (3.8 g) m 10 ml of dimethylformamide was slowly added After thirty minutes, the reaction mixture was stirred with 3 00 ml of ice-water and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to 5 5 g of an oil This material was purified by HPLC (silica, ethyl acetate) to give 4 6 g of an oil This oil was converted to the hydrochloride salt m 2 0 ml of warm isopropanol The product which precipitated upon cooling was collected and dried to give 3.8 g of crystals, m p 178-179°C ANALYSIS. Calculated for C33H17N3»HC1 Found 6?.02%C 62.03%C 7 21%H 7 27%H 16 69%N 16 61%N WO 97/04777 -25- PCT/US96/11408 EXAMPLE 7 U X 5 N-(2-Propenvl)-N-flH-pvrrol-l-vl)-4-pvridinamine hydrochloride To an ice-cooled suspension of sodium hydride (60% oil dispersion, 1 2 g, previously washed with hexanes) in 5 ml 10 of dimethylformamide was slowly added a solution of N-(1H-pyrrol-l-yl) -4-pyridinamine (4 g) m 25 ml of dimethylformamide After the anion formation, a solution of allyl bromide (3 1 g) m 5 ml of dimethylformamide was added After stirring cold for one hour, the reaction 15 mixture was stirred with water and extracted with ethyl acetate The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to 6 g of an oil This oil was purified by flash chromatography 20 (silica, ethyl acetate) to give 5 g of an oil This oil was converted to the hydrochloride salt and twice recrystallized from isopropanol/ether to give 3 5 g of crystals, m p 218-219°C 25 ANALYSIS. Calculated for C12H13N3*HC1 Found 61 14%C 61 04%C 5 99%H 17 83%N 6.16%H 17 78%N WO 97/04777 -26- PCT/US96/11408 EXAMPLE 8 U X 5 N-(2-Propvnvl)-N-(lH-pvrrol-l-vl)-4-pyridinamine hydrochloride To an ice-cold suspension of sodium hydride (60% oil dispersion, 3 g) m 10 ml of dimethylformamide was slowly 10 added N- (lH-pyrrol-l-yl) -4-pyridmamine (10 g) in 70 ml of dimethylformamide After the anion formation, a solution of propargyl bromide (80 wt % in toluene, 11 g) m 10 ml of dimethylformamide was slowly added After one hour, the reaction mixture was stirred with 500 ml of ice-water and 15 extracted with ethyl acetate The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to 20 g of oil this oil was purified by HPLC (silica, ethyl acetate-dichloromethane) to give 12 g of 20 oil A four gram sample was converted to the hydrochloride salt in 30 ml of warm isopropanol to yield, upon cooling, 3 3 g of solid, m p 224-225°C (dec ) This material was recrystallized from isopropanol to give 2 7 g of solid, m.p 230-231°C (dec ) 25 ANALYSIS Calculated for C^Hn^-RCl 61.67%C 5 18%H 17 98%N Found- 61.41%C 5 10%H 17 88%N WO 97/04777 -27- PCT/US96/11408 EXAMPLE 9 Tsl N- (2 -Chloro-lH-pvrrol-l-vl) -N-methvl-4-pvndinamine hydrochloride 5 To a solution of N-methyl-N-(lH-pyrrol-l-yl)-4- pyridinamme (7 7 g) m 300 ml of anhydrous tetrahydrofuran cooled to 5°C with an ice bath was added N-chlorosuccinimide (5 2 g) The reaction mixture was stirred sixty hours at ambient temperature, and thereafter ) additional N-chlorosuccinimide (0 9 g) was added After stirring an additional sixteen hours at ambient temperature, the reaction mixture was stirred with an aqueous solution of sodium bisulfite and extracted with ether The organic extract was washed with water and 5 saturated sodium chloride solution and thereafter dried over anhydrous magnesium sulfate, filtered and evaporated to 9 5 g of an oil This oil was purified by HPLC (silica, ethyl acetate) to give 4 4 g of an oil This oil was purified by column chromatography (alumina, ether) to give 0 2 4 g of the desired product as an oil This oil was dissolved m 25 ml of isopropanol, filtered, and converted to the hydrochloride salt by the addition of ethereal hydrochloric acid The solution was diluted with 25 ml of ether and cooled The resultant precipitate was collected 5 and dried to give 2 5 g of crystals, m p 230-231°C ANALYSIS Calculated for C10H10CIN3 *HCl 49 20%C 4 54%H 17 22%N Found- 49 15%C 4 67%H 17 34%N WO 97/04777 -28- PCT/US96/11408 EXAMPLE 10 Ut' N-(2-Chloro-lH-pvrrol-l-vl)-N-(4-pvndmvl)carbamic acid To a solution of N-(4-pyridmyl)-N-(lH-pyrrol-1-yl)carbamic acid ethyl ester (9 g) m 100 ml of anhydrous tetrahydrofuran warmed to 50°C was slowly dropped a solution of N-chlorosuccimmide (5.2 g) in 75 ml of 10 anhydrous tetrahydrofuran After stirring seven hours at 50°C, the reaction mixture was cooled, stirred with an aqueous solution of sodium bisulfite and extracted with ethyl acetate The organic extract was washed with water and saturated sodium chloride solution and thereafter dried 15 over anhydrous magnesium sulfate, filtered and evaporated to 11 5 g of an oil. This oil was purified by HPLC (silica, 20% ethyl acetate m dichloromethane) to give 3 8 g of the desired product as a solid This material was converted to the hydrochloride salt and twice 20 recrystallized from isopropanol-ether to give 3 3 g of crystals, m.p 139-140°C (dec ). ANALYSIS Calculated for C^H^Cl^C^ *HC1 47 70%C 4 34%H 13 91%N 5 ethvl ester hydrochloride 25 Found. 47 58%C 4 36%H 13 97%N WO 97/04777 -29- PCT/US96/11408 EXAMPLE 11 N- (2-Chloro-lH-pvrrol-l-vl)-N-ethyl-4-r>vridinamine hydrochloride 5 To a solution of N-ethyl-N-(lH-pyrrol-l-yl)-4- pyndinamme (10 2 g) m 2 00 ml of anhydrous tetrahydrofuran was added N-chlorosuccinimide (7 3 g) After stirring twenty hours at ambient temperature, the reaction mixture was stirred with an aqueous solution of 10 sodium sulfite and extracted with dichloromethane The organic extract was washed with water and saturated sodium chloride solution and thereafter dried over anhydrous magnesium sulfate, filtered and evaporated to 12 g of an oil This oil was purified by HPLC (silica, 25% 15 dichloromethane m ethyl acetate) to give 3.7 g of the desired product as an oil This oil was converted to the hydrochloride salt and twice recrystallized from isopropanol-ether to give 3 1 g of crystals, m p. 206-2 07°C 20 ANALYSIS Calculated for C11H12CIN3*HC1.51 18%C 5 08%H 16 28%N Found 51 43%C 4 95%H 16 36%N WO 97/04777 3°~ PCT/US96/11408 EXAMPLE 12 N- (2-Chloro-lH-pvrrol-l-yl) -N-pror>vl-4-pvridinamine hydrochloride 5 To a solution of N-propyl-N-(lH-pyrrol-l-yl)-4- pyridmamine (11 g) m 250 ml of tetrahydrofuran, cooled with an ice bath, was added N-chlorosuccinimide (8 g) as a powder The reaction mixture was warmed to ambient temperature and after sixteen hours additional N-10 chlorosuccinimide (1 g) was added After stirring for additional three hours, the reaction mixture was stirred with cold water, basified with sodium carbonate and extracted with ethyl acetate The organic extract was washed with water and saturated sodium chloride solution, 15 dried over anhydrous magnesium sulfate, filtered and evaporated to 14 g of oil This oil was purified by HPLC (silica, ethyl acetate-dichloromethane) to give 4 1 g of pure product as an oil. This oil was converted to the hydrochloride salt and recrystallized twice from 20 isopropanol-ether to give 2 4 g of crystals, m p 210-211°C ANALYSIS Calculated for C22H24CIN3 .RC1 52.95%C 5 56%H 15 44%N 25 Found. 52 76%C 5 40%H 15 25%N WO 97/04777 -31- PCT/US96/11408 "CI NH N-(2-Chloro-lH-Pvrrol-l-vl)-4-pvridinamine hydrochloride A mixture prepared from a solution of N-(2-chloro-lH-5 pyrrol-1-yl)-N-(4-pyridmyl)carbamic acid ethyl ester (6 g) m 50 ml of ethanol and 20 ml of 10% aqueous sodium hydroxide solution was warmed for 15 minutes on a steam bath, and thereafter cooled, diluted with 500 ml of water and extracted with dichloromethane The organic extract 10 was washed with water and saturated sodium chloride solution and thereafter dried over anhydrous magnesium sulfate, filtered and evaporated to 5 g of an oil This oil was purified by HPLC (silica, ethyl acetate) to give 3 5 g of a solid, m p 115-118°C This material was 15 converted to the hydrochloride salt and recrystallized twice from isopropanol-ether to give 3 4 g of crystals , m p. 172-173 °C. ANA^YSJIS, 20 Calculated for C9H8CIN3.HCI 46 98%C 3 94%H 18.27%N Found 46 76%C 3 80%H 18 13%N WO 97/04777 PCT/US96/11408 EXAMPLE 14 NT 2-Butvl-N-methvl-N-(lH-Pvrrol-l-vl)-4-pvridmamine maleate To a solution of N-methyl-N-(lH-pyrrol-l-yl)-4-5 pyndinantme (4.2 g) m 50 ml of anhydrous tetrahydrofuran cooled to -78°C under nitrogen, was slowly dropped n-butyllithium (2 1 molar m hexane, 13 8 ml) After the addition, the mixture was slowly warmed to ambient temperature After stirring thirty minutes at ambient 10 temperature, the reaction mixture was stirred with 3 00 ml of water and extracted with ethyl acetate The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to 8 2 g of an oil. This oil was purified 15 by HPLC (silica, 50% ethyl acetate-dichloromethane) to give 3 7 g of an oil This oil was dissolved m 25 ml of warm isopropanol, and filtered, and a solution of maleic acid (1 9 g) m isopropanol was added The crystals which formed upon cooling were collected and dried to give 5 g of 20 crystals, m.p 98-110°C. ANALYSIS Calculated for C14H19N3 *0411404 62 59%C 6 71%H 12 17%N Found 62 33%C 6 81%H 11 90%N 25 WO 97/04777 -33- PCT/US96/11408 EXAMPLE 15 N- (2-Ethvl-lH-pvrrol-l-vl) -N-methvl-4-r>vridinamine hydrochloride 5 A solution of N-(2-ethenyl-lH-pyrrol-l-yl)-N-methyl-4- pyridmamine (5 2 g) in 250 ml of ethanol containing 350 mg of platinum oxide was hydrogenated at 344.74 kilopascals (hereafter "KPa") [50 pounds per square inch (hereafter "psi")] for three hours and thereafter the product was 10 filtered and evaporated to 5 g of oil This oil was purified by flash chromatography (silica, 2 5% dichloromethane in ethyl acetate) to give 3 9 g of oil This oil was converted to the hydrochloride salt and recrystallized twice from isopropanol-ether to give 3.0 g 15 of crystals, m p 197-198°C 20 ANALYSIS Calculated for Ci2H15N3*HCl 60 62%C Found 60 32%C EXAMPLE 16 6.7 8%N 6 .77%H 17 68%N 17 54%N WO 97/04777 -34- PCT/US96/11408 10 N-Methvl-N- (2-propyl-lH-Pvrrol-l-vl) -4-pvridinamme hydrochloride A solution of N-[2-(1-propenyl)-lH-pyrrol-l-yl)-N-methyl-4-pyridinamme (7 h) in 250 ml of ethanol containing 350 mg of platinum oxide was hydrogenated at 344 74 Kpa 50 psi) for two days, and thereafter the product was filtered and evaporated to 9 g of oil This oil was purified by flash chromatography (silica, ethyl acetate) to give 8 g of oil This oil was purified by column chromatography (alumina, ether) to give 5 g of oil This oil was converted to the hydrochloride salt and recrystallized from isopropanol-ether and from ethanol-ether to give 2.8 g of crystals, m.p. 210-212°C 15 ANALYSIS, Calculated for C^I^^-HCl 62 02%C 7 21%H 16.69%N Found 61 92%C 7 24%H 16.64%N 20 25 EXAMPLE 17 Nf N- (4-Pvridinvl) -lH-mdol-l-amme maleate A solution of lH-mdol-l-amme (30 g) , 4-chloropyridme hydrochloride (34 g) and pyridine (18 g) m 250 ml of isopropanol was stirred at 85°C for 1 5 hours, and thereafter cooled, stirred with ice-water, basified with sodium carbonate and extracted with dichloromethane The organic extract was washed with water and saturated sodium chloride solution, was dried over anhydrous magnesium sulfate, filtered and concentrated to a dark oil WO 97/04777 -35- PCT/US96/11408 This oil was purified by flash chromatography (silica, ethyl acetate) f ' thereafter by column chromatography (alumina, ether/ to give 24 g of oil A 3 6 g sample was purified by high performance liquid chromatography (silica, 5 ethyl acetate) to give 3 5 g of oil This oil was converted to the maleate salt and recrystallized twice from methanol/ether to give 3 8 g of needles, m p 145-146°C (dec ). 10 ANALYSIS. Calculated for C13H11N3 *0411404 62.75%C 4 65%N 12 92%N Found 62 62%C 4 81%H 12 73%N 15 20 25 EXAMPLE 18 I nch3 tT N-Methvl-N- (4-pvridinvl) -lH-mdol-l-amme maleate A solution of N- (4-pyridinyl) -lH-indol-l-amme (7 4 g) in 3 0 ml of dimethylformamide was added to an ice-cooled suspension of sodium hydride (1 6 g of 60% sodium hydride dispersion m mineral oil was washed with hexanes, the liquid portion was decanted and the residual solid was dispersed m 10 ml of dimethylformamide). After anion formation, a solution of dimethylsulfate (5 g) in 10 ml of dimethylformamide was added After one hour of stirring at ambient temperature, the reaction mixture was stirred with ice-water and extracted with ether The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to 8 g of oil. This oil was purified by WO 97/04777 -36- PCT/US96/11408 flash chromatography (silica, ethyl acetate) and HPLC (silica, ethyl acetate) to give 2.9 g of oil This oil was converted to the maleate salt and was recrystallized twice from methanol/ether to give 2.1 g of crystals, m.p 103-5 104°C 10 15 25 ANALYSES, Calculated for C14H13N3 ^4^04 63.70%C 5 05%H Found 63 3 6%C 4.93%H 12 39%N 12 39%N 20 N-Ethvl-N-(4-pyridmyl)-lH-indol-1-amine maleate To an ice-cooled suspension of sodium hydride (1 7 g of 60% sodium hydride dispersion m mineral oil was washed with hexanes, the liquid was decanted and the residual solid was dispersed m 5 ml of dimethylformamide) was slowly added a solution of N- (4-pyridmyl) -lH-mdol-l-amme (7 6 g) in 25 ml of dimethylformamide After anion formation, a solution of diethyl sulfate (6 4 g) in 10 ml of dimethylformamide was slowly added After one hour, the mixture was stirred with ice-water and extracted with ethyl acetate The organic extract was washed with water and saturated sodium chloride solution, was dried over anhydrous magnesium sulfate, filtered and concentrated to 11 g of oil This oil was purified by flash chromatography (silica, ethyl acetate) to give 6 2 g of oil This oil was purified by column chromatography (alumina, ether) to give 6 g of oil A 3 g sample was convened to the maleate salt WO 97/04777 -37- PCT/US96/11408 and recrystallized from ethanol/ether and thereafter from methanol/ether to give 2 7 g of crystals, m p 119-120°C ANALYSIS. 5 Calculated for C15H15N3 ^4^04 • 64 58%C 5 42%H 11 89%N Found 64 27%C 5 49%H 12 11%N EXAMPLE 2 0 10 Part A. N-Propvl-N- (4-Pvridmvl) - lH-indol-l-amme maleate A solution of N- (4-pyridmyl)-lH-mdol-l-amine (6 g) in 25 ml of dimethylformamide was slowly added to an ice-cooled suspension of sodium hydride (1 3 g of 60% sodium hydride dispersion m mineral oil was washed with hexanes, 15 the liquid was decanted and the residual solid was dispersed in 5 ml of dimethylformamide) After anion formation, a solution of 1-bromopropane (4 g) in 5 ml of dimethylformamide was added After one hour of stirring at ambient temperature, the reaction mixture was stirred with 20 ice-water and extracted with dichloromethane The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to 8 g of oil This oil was purified by HPLC (silica, ethyl acetate) and thereafter by column 25 chromatography (alumina, ether) to give 6 4 g oil This oil was converted to the maleate salt and recrystallized form methanol/ether to give 6 8 g of crystals, m.p. 115-116°C WO 97/04777 -38- PCT/US96/11408 ANALYSIS Calculated for C16H17N3*0411404 65 3 8%C 5 76%H 11.44%N Found: 65 26%C 5 71%H 11 34%N 5 Part B N-Proovl-N- 14-Pvridmvl) -lH-mdol-l-amme hydrochloride The free base oil was converted to the hydrochloride salt which was recrystallized from methanol, m p 212-214°C 10 ANALYSIS Calculated for CigH^^-HCl 66 78%C 6 03%H 14 60%N Found. 66 77%C 6 39%H 14 59%N 15 EXAMPLE 21 5-Methoxv-N-propyl-N- (4-pyridmyl) -lH-indol-l-amme maleate To an ice-cooled suspension of sodium hydride (0 5 g of 60% sodium hydride dispersion m mineral oil was washed 20 with hexanes, the liquid was decanted and the residual solid was dispersed m 5 ml of dimethylformamide) was slowly added a solution of 5-methoxy-N-(4-pyridinyl)-1H-mdol-l-amine (2 3 g) m 20 ml of dimethylformamide After anion formation, a solution of 1-bromopropane (1 4 g) m 5 25 ml of diemthylformamide was added After one hour of stirring, the reaction mixture was stirred with ice-water and extracted with dicloromethane The organic extract was washed with water and saturated sodium chloride solution, WO 97/04777 -39- PCT/US96/11408 10 dried over anhydrous magnesium sulfate, filtered and concentrated to 2,3 g of oil This oil was purified by flash chromatography (silica, ethyl acetate) to give 2 1 g of oil. This oil was converted to the maleate salt m ethanol/ether to give 2.0 g of crystals, m p 138-139°C. ANALYSIS: Calculated for 63 46%C 5 83%H 10.58%N Found 63 26%C 5 77%H 10.47%N EXAMPLE 22 O Ah I nch3 N-Methvl-N- 14-nvridinvl) -lH-mdol-l-amine-3-carboxaldehvde maleate 15 To ice-cooled dimethylformamide (4 g) was slowly added phosphorous oxychloride (7 g) After complex formation, a solution of N-methyl-N- (4-pyridmyl) -lH-mdol-l-amine (5 g) in 50 ml of dichloroethane was added After one hour of stirring at 85°C, the reaction mixture was cooled, 20 hydrolyzed with a solution of sodium acetate (5 g) in 25 ml of water, again cooled, basified with sodium carbonate and extracted with dichloromethane The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and 25 concentrated to 6 g of oil This oil was purified by flash chromatography (silica, ethyl acetate) to give 4.6 g of oil This oil was converted to the maleate salt and WO 97/04777 -40- PCT/US96/11408 recrystallized from ethanol/ether and thereafter from methanol/ether to give 2 6 g of crystals, m.p 162-163°C (dec ) 5 analysis,. Calculated for Ci5H13N30»C4H404:62.12%C 4 66%H 11 44%N Found 61.71%C 4.62%H 11.14%N EXAMPLE 23 10 15 Ah 20 25 N-Ethvl-N-(4-pvridinvl)-lH-indol-l-amine-3-carboxaldehvde maleate To ice-cooled dimethylformamide (2 2 g) was slowly added phosphorus oxychloride (4 5 g) After complex formation, a solution of N-ethyl-N-(4-pyridmyl)-lH-indol-1-amme (3 5 g) in 50 ml of dichloroethane was added The mixture was stirred at 80° for one hour and thereafter hydrolyzed with a solution of sodium acetate (5 g) m 25 ml of water, cooled, basified with sodium carbonate and extracted with dichloromethane The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to 5 g of oil This oil was purified by flash chromatography (silica, ethyl acetate) to give 3 5 g of oil This oil was converted to the maleate salt and recrystallized form ethanol/ether and thereafter from methanol/ether to give 3 g of solid, m p 170-171°C (dec ) WO 97/04777 -41- PCT/US96/11408 ANALYSIS, Calculated for C15Hi5N30»C4H404 62 98%C 5 02%H 11.02%N 3-Ethenyl-N-methyl-N- (4 -pvridmvl) -1H-mdol-1-amine maleate To an ice-cooled suspension of 10 methyltriphenylphosphonium bromide (13 g) in 100 ml of anhydrous ether was added potassium tert-butoxide (4 g) After phosphorane formation, a solution of N-ethyl-N-(4-pyridmyl) -lH-mdol-l-amme-3-carboxaldehyde (7 5 g) m 50 ml of ether and 5 0 ml of tetrahydrofuran was added After 15 one hour of stirring, the reaction mixture was stirred with water and extracted with ether The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to 2 0 g of oil This oil was purified by 20 flash chromatography (silica, ethyl acetate) to give 7 g of oil A 3.5 g sample was converted to the maleate salt m ethanol and recrystallized from methanol ether to give 3 g of crystals, m p 153-154°C Found 62 97%C 5 08%H 11 06%N 5 EXAMPLE 24 25 ANALYSIS Calculated for C16H15N3.C4H4O4 65 74%C Found. 65 94%C 5 24%H 11 50%N 5 39%H 11 45%N WO 97/04777 -42- PCT/US96/11408 EXAMPLE 25 3-Ethvl-N-methvl-N- (4-pvridinyl) -lH-mdol-l-amine hydrochloride 5 A solution of 3-ethenyl-N-methyl-N-(4-pyridmyl)-1H- mdol-l-amine (5 g) m 250 ml of ethanol containing 0 5 g of platinum oxide was hydrogenated at 344 74 Kpa (50 psi) for one hour The mixture was filtered and the filtrate was concentrated to 5 g of oil This oil was purified by 10 flash chromatography (silica, ethyl acetate) to give 3 5 g of oil This oil was converted to the hydrochloride salt m ethanol/ether and recrystallized form methanol/ether to give 3 0 g of crystals, m p 262°C (dec.) 15 ANALYSIS, Calculated for CigH^^'HCl 66 77%C 6 30%H 14 60%N Found 66 87%C 6 33%H 14 57%N EXAMPLE 26 20 5-Chloro-N- (4-Dvridmvl)-lH-mdol-l-amine maleate WO 97/04777 -43- PCT7US96/11408 A solution of 5-chloro-lH-mdol-l-amine (9 g) , 4-chloropyridine hydrochloride (12 g) and pyridine (6.4 g) m 100 ml of isopropanol was stirred at reflux for one hour, cooled and stirred with ice-water, and the mixture was 5 basified with sodium carbonate, extracted with dichloromethane and filtered. The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to a dark oil This oil was purified by flash 10 chromatography (silica, ethyl acetate) to give 6 2 g of oil This oil was converted to the maleate salt m methanol-ether to give 7 g of crystals, m p 148-150°C A 2 6 g sample was recrystallized from methanol-ether to give 2 4 g of crystals, m.p 150-152°C 15 ANALYSIS Calculated for C^H] 0CIN3-C^C^ • 56 75%C 3 92%H 11 68%N Found: 56 71%C 4 00%H 11 62%N 20 EXAMPLE 27 5-Chloro-N-propvl-N- (4-Pvridmvl) -IH-mdol-l-amine maleate A solution of 5-chloro-N-(4-pyridinyl)-lH-mdol-1-amme (3 3 g) in 15 ml of dimethylformamide was slowly 25 added to an ice-cooled suspension of sodium hydride (0 65 g of 60% oil dispersion was washed with hexanes) m 5 ml of dimethylformamide After anion formation a solution of 1-bromopropane (2 g) m 5 ml of dimethylformamide was added. CI WO 97/04777 -44- PCT/US96/11408 After one hour the reaction mixture was stirred with ice-water and extracted with dichlormethane The organic extract was washed with water and saturated sodium chloride solution, was dried over anhydrous magnesium sulfate, 5 filtered and concentrated to 5 g of oil This oil was purified by flash chromatography (silica, ethyl acetate) to give 3 1 g of oil. This oil was converted to the maleate salt in ethanol-ether and thereafter recrystallized from methanol-ether to give 3.4 g of crystals, m p 13 0°C 10 ANALYSIS; Calculated for C15H16CIN3 *0411404 59 77%C Found 59 97%C 5 02%H 10 46%N 5 13%H 10 35%N 15 EXAMPLE 28 5-Bromo-N- (4-pvridmvl) -lH-indol-l-amme maleate A solution of 5-bromo-lH-mdol-l-amine (13 g) , 4-chloropyridme hydrochloride (14 g) and pyridine (7 2 g) m 20 100 ml of isopropanol was stirred at reflux for one hour, cooled and stirred with ice-water, and thereafter the mixture was basified with sodium carbonate, extracted with dichloromethane and filtered The organic extract was washed with water and saturated sodium chloride solution, 25 dried over anhydrous magnesium sulfate, filtered and concentrated to a dark oil This oil was purified by flash chromatography (silica, ethyl acetate) to give 11 g of oil This oil was converted to the maleate salt in ethanol-ether WO 97/04777 -45- PCTAJS96/11408 to give 13 g of solid, m p. 155-157°C dec A three gram sample was recrystallized from methanol-ether to give 2.8 g of crystals, m.p. 161-162°C (dec.). Calculated for C^H^oBr^ ^4*1404 . 50 . 51%C 3 49%H 10 40%N Found: 50 46tC 3 56%H 10 40%N 10 EXAMPLE 29 Br. 5-Bromo-N-methvl-N-(4-PvridinvI)-lH-mdol-l-amine maleate A solution of 5-bromo-N- I 4-Dvridmvl) - lH-mdol -1-am] ne A solution of 5-bromo-N- (4-pyridmyl)-lH-mdol-l-amme (2.7 g) m 20 ml of dimethylformamide was slowly added to an ice-cooled suspension of sodium hydride (0 45 g of 60% 15 oil dispersion was washed with hexanes) m 5 ml of dimethylformamide After anion formation a solution of dimethylsulfate (1.4 g) in 5 ml of dimethylformamide was added After one hour the reaction mixture was stirred with ice-water and extracted with dichloromethane The 20 organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to 2 g of oil This oil was purified by flash chromatography (silica, ethyl acetate) to give 1.4 g of oil. This oil was converted to the maleate 25 salt m ethanol-ether to give 1 2 g of crystals, m p 110-111°C WO 97/04777 -46- rCT/US96/11408 ANALYSIS > Calculated for C]_4Hi2BrN3 ^4^04 • 51 69%C 3 86%H 10.05%N Found. 51 55%C 3.89%H 10 14%N 5 EXAMPLE 30 5-Bromo-N-propyl-N- ( 4-pvridmyl) -lH-mdol-l-amine maleate A solution of 5-bromo-N- (4-pyridmyl) -lH-indol-l-amme (4 9 g) m 25 ml of dimethylformamide was slowly added to 10 an ice-cooled suspension of sodium hydride (0 8 g of 60% oil dispersion was washed with hexanes) m 5 ml of dimethylformamide After anion formation a solution of 1-bromopropane (2 5 g) in 5 ml of dimethylformamide was added After one hour the reaction mixture was stirred 15 with ice-water and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to 5 g of oil This oil was purified by flash chromatography (silica, ethyl acetate) to 20 give 4 5 g of oil. This oil was converted to the maleate salt in ethanol-ether to give 5 4 g of solid, m p 150-152° (dec,). This solid was recrystallized from methanol-ether to give 4 8 g of crystals, m p 157-158°C (dec ) 25 ANALYSIS Calculated for C^gH^gBr^ ^4^04 53 82%C 4.52%H Found: 53 63%C 4 62%H 9 42%N 9 40%N WO 97/04777 -47- PCT/US96/11408 EXAMPLE 31 5-Nitro-N-(4-pvrldinvl)-1H-indol-1-amine hydrochloride A solution of 5-nitro-lH-mdol-1-amine (4 5 g) and 4-5 chloropyridine hydrochloride (4.5 g) m 175 ml of isopropanol was stirred at reflux for two hours, another equivalent of 4-chloropyridine hydrochloride was added and the mixture was refluxed for two additional hours The reaction mixture was then cooled, stirred with water, 10 basified with sodium carbonate and extracted with ethyl acetate The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to 9 g of dark oil This oil was purified by flash chromatography 15 (silica, ethyl acetate) to give 3 8 g of light brown solid, m p 183-184°C This material was converted to the hydrochloride salt and recrystallized twice from methanol/ether to give 3 5 g of orange needles, m p 3 00-302°C (dec ) 20 ANALYSIS. Calculated for -HCl 53 71%C 3 81%H 19.28%N Found- 53 55%C 3 77%H 19.17%N WO 97/04777 -48- PCT/US96/11408 EXAMPLE 32 nch3 N-Methvl-5-nitro-N- (4-Pvndinvl) -lH-mdol-l-amme maleate A solution of 5-nitro-N-(4-pyridinyl)-lH-indol-l-amine 5 (6 g) in 20 ml of dimethylformamide was slowly added to an ice-cooled sodium hydride suspension prepared by washing 1.2 g of 60% sodium hydride suspension in oil with hexanes and suspending the residue m 5 ml of dimethylformamide After the anion formation a solution of dimethyl sulfate 10 (3 7 g) in 10 ml of dimethylformamide was added After one hour the reaction mixture was stirred with water and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and 15 concentrated to 6 g of dark oil This was purified by flash chromatography (silica, ethyl acetate) to give 2.7 g of orange solid, m p 149-150°C This was converted to the maleate salt and recrystallized twice from methanol/ether to give 2 7 g of orange crystals, m p 174-175°C (dec ). 20 ANALYSTS Calculated for C14H22N4O2^4^04 56.25%C 4.20%H 14.58%N Found 56 14%C 4 27%H 14 46%N WO 97/04777 -49- PCT/US96/11408 3-Methvl-N-(4-pvridinvl)-lH-mdol-l-amine oxalate To 2 00 ml of isopropanol were added 4-chloropyridine 5 hydrochloride (7 5 g) and 3-methyl-lH-indol-l-amme (7 6 g) The mixture was stirred at 90°C for six hours, and thereafter poured into 400 ml of ice water, and stirred for five minutes The pH was adjusted to 10 with sodium carbonate solution and then extracted with ethyl acetate 10 The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to obtain 8 4 g of thick brown oil, which was eluted on a silica gel column with ethyl acetate via HPLC The desired fractions were combined and concentrated to 7 4 g of brown 15 oil A 2.3 g sample of this oil was dissolved m 50 ml of ethanol, and the pH adjusted to 1 with an ethanolic solution of oxalic acid, and the solution was diluted with ether The resultant white precipitate was collected and dried to give 4 0 g, m p 130-135°C (dec ) This material 20 was recrystallized from ethanol/ether (1.1) to give 3 8 g, m.p 137°C (dec ) ANALYSIS. Calculated for Ci4H13N3.C2H204 61.33%C 4 83%H 13 41%N 25 Found 61 41%C 4 96%H 13 28%N WO 97/04777 " 5 ° " PCT/US96/11408 EXAMPLE 3 4 3-Methyl-N-propvl-N-(4-pyndmvl)-lH-indol-l-amme maleate To a cold sodium hydride suspension prepared by 5 washing 0 8 g of 60% sodium hydride suspension m oil with hexanes and suspending the residue m 15 ml of dry dimethylformamide was added a solution of 3-methyl-N-(4-pyridmyl) -lH-indol-l-amme (4 0 g) m 25 ml of dry dimethylformamide m ten minutes After ten minutes a 10 solution of propyl bromide (2 7 g) in 15 ml dimethylformamide was added The mixture was stirred at ambient temperature for thirty minutes, poured into 200 ml of ice water, stirred for five minutes, and then extracted with ethyl acetate The organic layer was washed with 15 water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 5 g of brown oil, which was eluted on a silica gel column with ethyl acetate via HPLC The desired fractions were combined and concentrated to 2 6 g of brown oil This oil was dissolved in ether, the pH 20 was adjusted to 1 with ethereal maleic acid, and the resultant white precipitate collected and dried to give, 4 0 g m p 148°C (dec ) This material was recrystallized from methanol/ether (1:10) to give 3 5 g of white crystals, m p 148-149°C 25 ANALYSIS t Calculated for Ci7H19N3.C4H4O4 66 13%C 6 08%H 11 02%N Found 66 15%C 6 02%H 11 00%N WO *>7/04777 -51- PCT/IIS96/11408 EXAMPLE 3 5 N- (3-Fluoro-4--pvridinvl) -3-:methvl-lH-indol-l-amine To 200 ml of isopropanol were added 4-chloro-3-5 fluoropyridme hydrochloride (10 g) and 3-methyl-lH-mdol-amine (5 9 g) The mixture was stirred at 90°C for four hours, cooled, and poured into 500 ml of ice water The pH was adjusted to 10 with sodium carbonate solution, and the mixture was extracted with ethyl acetate The organic 10 layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to give about 10 g of dark oil, which was eluted on a silica gel column first with dichloromethane, and then with ether/petroleum ether (1 1) via flash chromatography The desired 15 fractions were combined and concentrated to a yellow solid, 6 2 g, m.p 45°C A sample of this material was recrystallized from isopropyl ether/hexanes (1:1) to give a yellow solid, m p 141-142°C 20 ANALYSIS Calculated for C14H12FN3 69.69%C 5 02%C 17 42%N Found 69 52%C 5 01%H 17 57%N WO 97/04777 -52- PCT/11S96/11408 EXAMPLE 3 6 N-(3-Fluoro-4-pvridinvl)-N-propvl-3-methvl-lH-indol-l-amme hydrochloride 5 To a sodium hydride suspension prepared by washing 0 5 g of 60% sodium hydride suspension in oil with hexanes and suspending the residue m 10 ml of dimethylformamide, was added a solution of N-(3-fluoro-4-pyridmyl)-3-methyl-lH-indol-1-amine (3 0 g) m 20 ml of dimethylformamide at lce-10 bath temperature over ten minutes The mixture was stirred for an additional five minutes, and thereafter a solution of propyl bromide (1 2 ml) m 10 ml of dimethylformamide was added m five minutes The mixture was stirred at ambient temperature for thirty minutes, poured into 10 ml 15 of ice-water, and then extracted with ethyl acetate The organic layer was collected, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to give 4 g of brown oil, which was eluted on a silica gel column with 20% ethyl acetate/dichloromethane 20 via HPLC The desired fractions were combined and concentrated to a thick yellow oil, 3 4 g. The oil was dissolved m ether, the pH adjusted to 1 with ethereal hydrogen chloride, and the resultant white precipitate collected and dried to give 3.4 g This material was 25 recrystallized from ethanol/ether (1 20) to give 2 7 g of white crystals, m.p 193°C (dec.) WO 97/04777 -53- PCT/US96/11408 ANALYSIS. Calculated for C17H18FN3*HC1 63 84%C 5.99%H 13 14%N Found. 64 11%C 6.01%H 13 20%N fvi N-(3-Fluoro-4-pvridmvl)-N-oropvl-lH-indol-l-amme hydrochloride To a sodium hydride suspension prepared by washing 0.6 10 g of 60% sodium hydride suspension in oil with hexanes and suspending the residue in 10 ml of cold dimethylformamide, was added a solution of N- (3-f luoro-4-pyridmyl) -lH-mdol-1-amme m 25 ml of dimethylformamide The mixture was stirred at 5°C for ten minutes, and thereafter a solution 15 of bromopropane (1 4 ml) in 10 ml of dimethyl formamide was added The mixture was stirred at ambient temperature for thirty minutes, poured into 200 ml of ice water, stirred for five minutes, and extracted with ethyl acetate The organic layer was washed with water and brine, dried over 20 anhydrous magnesium sulfate, filtered and evaporated to give 3 2 g of brown oil, which was eluted on a silica gel column with 10% ethyl acetate/dichloromethane via HPLC The desired fractions were combined and concentrated to 2 4 g of brown oil, which was dissolved in 4 0 ml of absolute 25 ethanol The pH was adjusted to 1 with ethereal hydrogen chloride and the solution was diluted with 400 ml of ether The resultant off-white precipitate was collected and dried to give 2.1 g, m p 198-200°C (dec ). WO 97/04777 -54- PCT/US96/11408 ANALYSIS Calculated for C16H16FN3-HCl• 62.85%C 5 60%H 13 74%N Found- 62 80%C 5 60%H 13 66%N EXAMPLE 3 8 NT 2-Methvl-N- (4-Pvridinvl) - lH-mdol-l-amine The title compound was prepared from 2-methyl-1H-indol-1-amme and 4-chloropyridine hydrochloride at 120°C 10 for 30 minutes in substantially the same manner as m Example 17, mp. 75-78°C 15 analysis Calculated for C14H13N3 Found 75 31%C 75 02%C 5 87%H 5 88%H 18 82%N 18 66%N EXAMPLE 39 N- (3-Methvl-4-pvridmvl) -lH-indol-l-amme 20 The title compound was prepared from lH-mdol-l-amme and 4-chloro-3-methylpyridme hydrochloride m isopropanol WO 97/04777 -55- PCT/US96/11408 at 90°C for 6 hours in substantially the same manner as in Example 17, m.p 78-80°C ANALYSIS; 5 Calculated for C14H13N3• Found 75.31%C 74 98%C 5 87%H 5 83%H 18.82%N 18.86%N EXAMPLE 4 0 10 N- ( 3-Methvl-4-pvndinvl) -N-propvl-lH-indol-l-amme oxalate The title compound was prepared from N-propyl-lH-mdol-l-amme and 4-chloro-3-methylpyridme hydrochloride m l-methyl-2-pyrrolidmone at 120°C for 20 hours m substantially the same manner as m Example 17, m p 155°C 15 (dec ) 20 ANALYSIS. Calculated for C^H^g^ *C2H204 64 21%C 5 96%H Found 64.15%C 5 85%H EXAMPLE 41 1ST 11 82%N 11 69%N WO 97/04777 -56- PCT/US96/11408 N- n-Pluoro-4-pvridinvl) -lH-indol-l-amme hydrochloride The title compound was prepared from lH-indol-l-amme and 4-chloro-3-fluoropyndine hydrochloride m isopropanol at 90°C for 4 hours in substantially the same manner as m Example 17, m.p >250°C 10 15 ANALYSIS; Calculated for C]_3H]_oFN3 *HC1 • 59 21%C Found 59 35%C 4 21%H 4 36%H 15 93%N 15 81%N N-(3-Chloro-4-pvridinvl)-lH-mdol-l-amine hydrochloride The title compound was prepared from lH-mdol-l-amine and 3,4-dichloropyridine hydrochloride m isopropanol at 100°C for 4 hours m substantially the same manner as m Example 17, m p >230°C 20 ANALYSIS Calculated for C13H20CIN3 *HC1. 55 73%C Found- 55 97%C 3 96%H 4.23%H 15 00%N 14 64%N WO 97/04777 -57- PCT/US96/11408 EXAMPLE 43 N-f 3-Fluoro-4-pyridmyl)-2-methvl-lH-indol-l-amme The title compound was prepared from 2-methyl-lH-indol-l-amine and 4-chloro-3-f luoropyndme hydrochloride m 1-methyl-2-pyrrolldone for 1 hour m substantially the same manner as m Example 17, m p 157-158°C ANALYSIS. 10 Calculated for Ci4H2,2FN3 Found. 69 69%C 69 53%C 5.02%H 4.95%H 17 42%N 17 28%N EXAMPLE 44 15 N- (3-Chloro-4-pvndinvl) - 3-methvl-lH-indol-1-amine hvdrochloride The title compound was prepared from 3-methyl-1H-mdol-l-amme and 3, 4-dichloropyridme hydrochloride m isopropanol at 80°C for 5 hours m substantially the same 20 manner as in Example 17 Recrystallized from ethanol, m p 278-280°C (dec.). WO 97/04777 -58- PCT/US96/11408 ANALYSIS, Calculated for C2.4H12CIN3 «HC1 57.16%C 4 45%H 14 29%N Found 57 20%C 4.44%H 14 28%N EXAMPLE 4 5 N-propvl-N-(4-pvridinvl)-lH-mdol-l-amme-3-carboxaldehvde maleate The title compound was prepared from N-propyl-N-(4-10 pyridmyl) -lH-mdol-l-amme, phosphorous oxychlonde and dimethylformamide m substantially the same manner as m Example 22, m p. 169-171°C ANALYSIS 15 Calculated for C17H17N30-C4H404 63.79%C 5.35%H 10.63%N Found 63.67%C 5.38%H 10 58%N EXAMPLE 46 20 N-Propyl-N- (4-py-ndinvl) -3-ethenvl-lH-mdol-l-amine mal eate WO 97/04777 -59- PCT/US96/11408 The title compound was prepared from N-propyl-N-(4-pyridmyl) -lH-mdol-l-amme-3 -carboxaldehyde, methyltriphenylphosphonium bromide and potassium-t-butoxide in substantially the same manner as in Example 24 5 Recrystallized from methanol/ether, m p. 157-158°C (dec.) ANALYSIS Calculated for C18H19N3 ^4^04 67.16%C 5.89%H 10 68%N Found- 66.73%C 6 40%H 10 56%N 3-Ethvl-N-propvl-N-(4-Pvridmvl)-lH-indol-l-amine maleate The title compound was prepared by hydrogenatmg 3-15 ethenyl-N-propyl-N- (4-pyridmyl) -lH-mdol-l-aiuine in substantially the same manner as m Example 25, m p 133-134°C. ANALYSIS 20 Calculated for CigH2iN3*C4H404 66 82%C 6 37%H 10 63%N Found: 66 73%C 6 40%H 10 62%N 10 EXAMPLE 47 WO 97/04777 -60- PCT/US96/11408 EXAMPLE 4 8 N-Butvl-N-(4-Pvndinvl)-lH-mdol-l-amine maleate The title compound was prepared from N- (4-pyridmyl) -5 lH-mdol-l-amine and 1-bromobutane with the aid of sodium hydride m substantially the same manner as m Example 20 Recrystallized from ethanol/ether (1:10), m p 108-110°C Am-Ys.ig,, 10 Calculated for C17H19N3-0411404 66 13%C 6.08%H 11 02%N Found 66 10%C 6.05%H 11 04%N EXAMPLE 49 15 N- (2-Propvnyl) -N- (4-pvridinvl) -lH-mdol-l-amine maleate The title compound was prepared from N-(4-pyridmyl) -lH-mdol-l-amme and propargyl bromide with the aid of sodium hydride m substantially the same manner as in Example 20 Recrystallized from ethanol/ether, m p 107-20 109 °C WO 97/04777 -61- PCT/US96/11408 ANALYSIS, Calculated for C16H13N3^4^04•66.11%C 4 72%H 11 56%N N- (2-Methvlpropvl) -N- (4-pvndinvl) -lH-mdol-l-amme maleate The title compound was prepared from N-(4-pyridmyl)-lH-indol-l-amine and l-bromo-2-methylpropane with the aid 10 of sodium hydride in substantially the same manner as m Example 20, m p 101-103°C. ANALYSIS Calculated for Ci7H19N3•C4H4O4 66.13%C 6 08%H 11 02%N 15 Found 66.03%C 6.09%H 11 01%N Found: 66.04%C 4.69%H 11.45%N 5 EXAMPLE 50 EXAMPLE 51 N-Pentyl-N- (4-pvridmvl) -lH-indol-l-amme maleate 20 The title compound was prepared from N- (4-pyridmyl) - IH-mdol-l-amine and 1-bromopentane with the aid of sodium WO 97/04777 ~62~ PCT/US96/11408 hydride in substantially the same manner as in Example 2 0 Recrystallized from ethanol/ether (1.9), m.p 91-93°C. ANALYSIS: 5 Calculated for C18H21N3-C^H^ : 66. 82%C 6.37%H 10 63%N Found 66 70%C 6.29%H 10.55%N EXAMPLE 52 10 15 N- (1-Methvlpropyl) -N- ( 4-pvridmvl) -lH-mdol-l-amine maleate The title compound was prepared from N- (4-pyridmyl) -lH-mdol-l-amme and 2-bromobutane with the aid of sodium hydride in substantially the same manner as m Example 20 Recrystallized from ethanol/ether, m.p 117-118°C ANALYSIS. Calculated for ^71^9^^411404 66 13%C 6 08%H 11 02%N Found: 65 78%C 5 97%H 10,98%N N- (1 -Me thyl ethyl) -N- (4-pyridmvl) - lH-mdol-l-amme maleate WO 97/04777 -63- PCT/US96/11408 The title compound was prepared from N-(4-pyridinyl)-lH-indol-1-amine and 2-bromopropane with the aid of sodium hydride in substantially the same manner as in Example 2 0 Recrystallized from methanol/ether, m.p. 121-123°C. MftkYSXS, Calculated for C16H17N3 -C^Cty 65 38%C 5.76%H 11 44%N Found: 65 28%C 5 81%H 11.36%N 10 EXAMPLE 54 15 20 2-Methvl-N-nropvl-N- (4-pvndinvl) -lH-mdol-l-amme maleate The title compound was prepared from 2-methyl-N-(4-pyndmyl)-lH-mdol-l-amme and 1-bromopropane with the aid of sodium hydride m substantially the same manner as in Example 20, m p. 155-156°C (dec ) ANALYSIS' Calculated for C17H19N3»C4H404:66 13%C 6.08%H 11 02%N Found: 65 78%C 6 08%H 10 82%N EXAMPLE 55 V WO 97/04777 -64- PCT/US96/11408 N-(3-Fluoro-4-pvndinvl)-N-(2-propenvl)-3-methvl-lH-indol- 1-amine hydrochloride The title compound was prepared from N-(3-fluoro-4~ pyridinyl)-3-methyl-lH-indol-l-amine and allyl bromide with 5 the aid of sodium hydride in substantially the same manner as m Example 20, m.p. 185-187°C. ANALYSIS, Calculated for C17H16FN3.HCl: 64.25%C 5.39%H 13 22%N 10 Found 64.15%C 5 39%H 13 08%N 15 EXAMPLE 56 N- ( 3 -Chioro-4 -pvndmvl) -N-pror>vl -1H- mdol -1 -amine hydrochloride The title compound was prepared from N-(3-chloro-4-pyridmyl)-lH-mdol-l-amme and propyl bromide with the aid of sodium hydride in substantially the same manner as in Example 20, m p 202°C (dec ). 20 ANALYSIS Ci5HI6C1N3.HC1 Found 59 63%C 60.01%C 5 32%H 5 31%H 13.04%N 12.94%N WO 97/04777 -65- PCT/US96/11408 EXAMPLE 57 n ■F N- (3-Fluoro-4--Dvridinvl) -N- (2-propvnvl) -lH-indol-l-amine hydrochloride pyridmyl) -lH-mdol-l-amme and propargyl bromide with the aid of sodium hydride in substantially the same manner as m Example 20 Recrystallized from methanol/ether (1 5), m p 211-212°C. 10 ANALYSIS. Calculated form C16H12FN3»HC1•63 68%C 4.34%H 13 93%N Found 63.46%C 4.20%H 13 72%N 15 EXAMPLE 58 N- (3-Fluoro-4-pvridinvl) -3-xnethvl-N- (2-propvnvl) -lH-mdol- 1-amine hydrochlpride The title compound was prepared from N-{3-fluoro-4-20 pyridmyl)-3-methyl-lH-mdol-l-amme and propargyl bromide with the aid of sodium hydride in substantially the same 5 The title compound was prepared from N-(3-fluoro-4- WO 97/04777 uwh -66- PCT/US96/11408 manner as an Example 20 Recrystallazed from methanol/ether {1- 5), m p 206-207°C 5 Calculated for C17H14FN3-HCl• 64 66%C 4 79%H 13.30%N Found: 64 49%C 4.70%H 13.18%N EXAMPLE 59 10 N-(3-Fluoro-4-Pvridinvl)-2-methvl-N-propvl-lH-indol-l-amine The title compound was prepared from N-(3-fluoro-4-pyridmyl)-2-methyl-lH-indol-l-amme and 1-bromo-propane with the aid of sodium hydride in substantially the same manner as m Example 20, m p 5°C 15 ANALYSIS Calculated for C17H1sFN3 72 06%C 6 40%H Found: 71 76%C 6 51%H 14 83%N 14 4 8%N 20 EXAMPLE 6 0 CI V" N- (3-Chloro-4-pyridmyl) -3-methyl-N-propyl-lH-mdol-l-amme WO 97/04777 -67- PCTYUS96/11408 The title compound was prepared from N-(3-chloro-4-pyridmyl)-3-methyl-lH-indol-l-amine and 1-bromo-propane with the aid of sodium hydride m substantially the same manner as in Example 20, m p. 68-70°C Calculated for C17H3.8CIN3: 68 10%C 6 05%H 14.02%N Found 67 99%C 6.01%H 14 01%N W-(3-Fluoro-4-pvndmvl)-N-(2-propenyl)-lH-indol-l-amme hydrochloride To a cold solution of N- (3-f luoro-4-pyridmyl)-1H-mdol- 1-amme (2 9 g) m 70 ml of dry tetrahydrofuran was added potassium tert-butoxide (1 7 g), and the mixture was stirred at 0°C for two minutes To this was added a solution of allyl bromide (1 3 ml) in 10 ml of tetrahydrofuran. After stirring at 0°C for 2 hours, the mixture was poured into 100 ml water, stirred for 5 minutes and extracted with ethyl acetate (3x). The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil (3 0 g) which was eluted on a silica gel column with 50% ethyl acetate/dichloromethane via HPLC The desired fractions were combined and concentrated to an oil (2 0 g) which was dissolved m ethanol The pH was adjusted to 1 with ethereal hydrogen chloride and the solution was EXAMPLE 61 WO 97/04777 -68- PCT/US96/11408 diluted with ether. The resultant precipitate was collected and dried to give 2 0 g of the title compound, m.p, 204-205°C. 5 ANALYSISi Calculated for C16H14FN3-HCl• 63 26%C 4 98%H 13.83%N Found 63.25%C 4.98%H 13 70%N EXAMPLE 62 4- fN- (lH-mdol-l-vl) 1 -3 . 4-pvndinamme hemihvdrate To a slurry of 10% palladium on carbon (1 Og) in 5 ml absolute ethanol was added N- (lH-mdol-l-yl) -3 -nitro-4-pyridmamine (5 Og) m 245 ml of absolute ethanol The 15 mixture was hydrogenated (Parr apparatus)at 344 74 Kpa (50 psi)for two hours The mixture was filtered and the filtrate evaporated to yield a brown oil (5 4g) which was eluted with 5% methanol/dichloromethane on a silica gel column via HPLC. The fractions containing product were 20 evaporated to yield a solid (3 8g) which was eluted with 5% methanol/dichloromethane on silica gel column via HPLC The desired fractions were evaporated to yield 2 5g of the title compound as a solid, m p 74-80°C. 25 ANALYSIS Calculated for C^H^N^O 5H20 Found. 66 93%C 5.62%H 67.31%C 5.22%H 24 04%N 23 98%N WO 97/04777 -69- FCT/US96/II408 EXAMPLS <?3 CI NH 3-Chloro-N-(4-pvridinvl)-1H-indol-1-amine sallcvlate A suspension of crude 3-chloro-lH-indol-l-amine 5 (65 5g) and 4-chloropyridine hydrochloride (45g) in 1- methyl-2-pyrrolidinone (250ml) was stirred at 60°C for eight hours The cooled reaction mixture was quenched into 5% aqueous sodium hydroxide, extracted into toluene, dried and concentrated to give an oil A portion of this oil was 10 dissolved in ethyl acetate Salicylic acid (1 2eq) was added to precipitate the salt. The solid was collected at room temperature and dried This solid was recrystallized with a charcoal treatment from methanol and oven dried (75°C, house vacuum) overnight to yield 10 9 g of the title 15 compound as a solid, m p 185-186°C (dec ) AnaJ-ygas, Calculated for C30H16N3O3Cl 62 91%C 4 22%H 11 01%N Found 62 74%C 4 12%H 10 93%N 20 EXAMPLE 64 NT -70- I'Ci/USy6/11408 WO 97/04777 3-Chloro-M-nropvl-N-(4-pvridmvl)-lH-l-amme hydrochloride To a cold (-10°C) solution of 3 - chloro-N-4-pyridmyl-IH-mdol-l-amme (4 5g) m dry dimethylformamide (36ml) was added potassium tert-butoxide (2.3g) portionwise to 5 maintain a temperature of approximately -1D°C After ageing at 0°C for one hour, a solution of 1-bromopropane (2 2 ml) m dry dimethylformamide (8 8 ml) was added, maintaining a temperature of approximately 0°C After stirring at 0°C for three hours, the reaction mixture was quenched with water, 10 extracted into ethyl acetate, dried and concentrated to give a dark oil A portion of this oil was purified by flash chromatography on silica gel using 9 1 dichloromethane/methanol as the elutmg solvent The fractions which contained product were combined, treated 15 with charcoal and concentrated to give an oil. A portion of this oil was dissolved m ether and ethereal hydrogen chloride was added to precipitate the salt This salt was isolated at room temperature and suction dried The solid was dissolved m methanol and methyl-tert-butyl ether was 20 added to precipitate the product The solid was isolated at room temperature and dried (7 0°C) under house vacuum to yield 3 7g of the title compound as a solid, m p 257-260°C (dec ) 25 Analysis • Calculated for ClsH17N3Cl2 Found 59 64%C 5 32%H 13 04%N 59.71%C 5 35%H 12.93%N WO 97/04777 -71- PCI/US96/114U8 EXAMPLE 6 5 5 N- (n-Propyl) -N- (4-r>vrxdmvl) -lH-indol-l-amine-3 -carboxaldehvde oxime maleate To a solution of N- (n-propyl) -N- ( 4-pyridmyl)-1H- indol-l-amine-3-carboxaldehyde (10 g) m 100 ml pyridine was added hydroxylamme hydrochloride (5 g) After stirring one hour at ambient temperature the reaction mixture was evaporated and the residue was stirred with 10 water, basified with sodium carbonate and extracted with ethyl acetate-ether The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to 12 g of oil This oil was purified by flash chromatography 15 (silica, ethyl acetate) to give 10.3 g of oil A portion (3 5 g) of this oil was converted to the maleate salt m ethanol-ether to give 4 g of the title compound as a solid This solid was recrystallized from ethanol-ether to give 3 5 g of solid, m.p 155-156°C 20 Analysis. Calculated for C21H22N405 : Found- 61 46%C 5.40%H 13 65%N 61 39%C 5.24%H 13 34%N WO 97/(M"777 ^ PCT/US96/11408 EXAMPLE 66 3-Aminomethvl-N-propvl-N- (4-pvndxnvl) -lH-indol-l-amme dihvdrochloride 5 A solution of N-propyl-N- (4-pyridmyl)-lH-indol-1- amme-3-carboxaldehyde oxime (5 5 g) an 100 ml 95% ethanol was quickly treated with Raney alloy (7 3 g, 50.50 Al/Ni alloy) and then with a solution of sodium hydroxide (7.8 g) dissolved in 100 ml water The exothermic reaction which 10 initiated was controlled with a reflux condenser The mixture cooled to ambient temperature and stirred for two hours The Raney alloy catalyst (pyrophoric) was removed by filtration and was washed with 50% aqueous ethanol The filtrate was concentrated to remove the ethanol and the 15 aqueous residue was extracted with dichloromethane The organic extract was washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to 4 7 g of oil. This was combined with 0 9 g product obtained from a trial reduction and the 20 combined product was purified by flash chromatography (silica, 2 0% methanol m dichloromethane) to give 4 3 g of oil This oil was converted to the dihydrochloride salt in methanol and the solution was concentrated to a residue The residue was recrystallized twice from 2 0% methanol in 25 acetonitrile to yield 2 9 g of the title compound as a solid, m p 254-256°C. WO 97/04777 -73- PCT/US96/11408 Analysis, Calculated for CnH,3Cl2N4 Found. 57.79%C 6 28%H 15.86%N 57.69%C 6 05%H 15.85%N 5 EXAMPLE 67 NH 3-Cvanomethyl-N- (4-pyridmvl) -1H- mdol-1-amine 3-Cyanomethyl-lH-mdol-l-amme (12 g) and 4- 10 chloropyridine hydrochloride (12 g) were combined in isopropanol (250 ml) After stirring at reflux (90°C) for six hours, the mixture was poured into water (500 ml) and stirred five minutes Thereafter the pH of the mixture was adjusted to 10 with sodium carbonate and the mixture was 15 extracted with ethyl acetate (2x) The organic layer was washed with water (2x), brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give an oil (22 g) This oil was eluted on a silica gel column with ethyl acetate Fractions containing product were combined 20 and concentrated to an oil (16 g) which solidified upon standing A portion of this solid was recrystallized from ethanol/ether (1.20) to give the title compound as a solid (2 g), m p 152-153°C 25 Analysis Calculated for Cl5H12N4 72 56%C 4 87%H 22 57%N Found 72 41%C 4 86%H 22 16%N WO 97/04777 -74- PCT/US96/11408 EXAMPLE 68 3-Aminoethvl-H- 14-nvndinyl) -lH-mdol-l-amine dimaleate To a solution of 3-cyanomethyl-N-(4-pyridinyl)-1H-5 mdol-1-amine (3 0 g) in 95% ethanol (80 ml) was added Raney alloy (4 2 g, 50%A1/Ni) followed by the dropwise addition of an aqueous solution of sodium hydroxide (6 0 g) m water (85 ml) A mild exotherm resulted and the mixture was stirred at ambient temperature for two hours 10 Thereafter the mixture was filtered and the filtrate was diluted with water (100 ml) This mixture was extracted with ethyl acetate (3x) The organic layer was washed with water (2x) and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil (2 4 g). This 15 oil was eluted on a silica column with 25% methanol/dichloromethane via flash chromatography to give a solid (2 2 g). This material was dissolved m hot ethanol, acidified to pH 1 with ethanolic maleic acid and thereafter diluted with ether. The resultant precipitate was 20 collected and dried to give the title compound as a solid (4 2 g), m.p 163°C (dec) 25 Analysis• Calculated for C15H16N »2C4H404 57 02%C Found- 56 87%C 4.99%H 11.57%N 5 04%H 11 42%N WO 97/04777 -75- PCT/US96/11408 EXAMPLE 6 9 I 3-Fl-uoro-N-propvl-N-(lH-Pvrrol-l-vl)-4-pyridinamine hydrochloride 5 A suspension of sodium hydride (0 8 g of a 60% suspension m oil washed with hexanes) m dimethylformamide (2 0 ml) which had been cooled to 5°C was added to a solution of 3-fluoro-N- (IH-pyrrol-l-yl)-4-pyridinamme (3 5 g) m dimethylformamide (25 ml) After stirring at 5°C for 10 fifteen minutes, a solution of propyl bromide (1 8 ml) m dime thyl formamide (20 ml) was added The mixture was stirred at ambient temperature for thirty minutes Thereafter the mixture was poured into ice-water (200 ml), stirred for five minutes and extracted with ethyl acetate 15 The organic layer was then washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil (4 0 g) This oil was eluted on a silica gel column with ethyl acetate via HPLC The fractions containing product were evaporated to an oil (3 6 20 g) This oil was dissolved m ethanol (200 ml) and acidified to pH 1 with ethereal hydrogen chloride. The resultant precipitate was collected and dried to give a solid (2.5 g), m p 194-5°C 25 Analysis- Calculated for C12HUFN3»HC1 • 56.3 6%C 5 91%H 16 43%N Found: 56.21%C 5 87%H 16 39%N AVO 97 mm -76- PCT/US96/11408 ct- (5-Chloro-pvridi.n-3.-vl) -1H-mdol-1 -amine Potassium tert-butoxide (12 7) was added to a 0°C 5 solution of N-aminoindole (6.0 g) in l-methyl-2- pvrrolidmone (150 ml) . After stirring for thirty minutes 3,5-dichloropyridine (7 5 g) was added and the resulting mixture was stirred at room temperature for five hours The reaction mixture was quenched with water, diluted with 10 ethyl acetate (500 ml) and washed with brine (3 x 500 ml) The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give an oil Purification of the oil by flash chromatography (silica, 0-2% methanol/dichloromethane) afforded the title compound (11 15 g) , m.p 154-156°C Analysis. Calculated for C13H10ClN3: 64 07%C 4 14%H 14 55%C1 17.24%N 20 Found. 63 77%C 4 14%H 14 63%C1 17.21%N WO 97/04777 -77- PCT/US96/11408 EXAMPLE 71 I NH N-(3-Pvndmvl)-lH-indol-l-amme Ten percent palladium on carbon (1 35 g) was added to 5 a solution of (5-chloro-3-pyridmyl)-lH-mdol-l-amme (5 8 g) m 3 1 ethanol/ethyl acetate (20 ml) and the resulting suspension was hydrogenated at 344 74 Kpa (50 psi, Parr shaker) for forty-eight hours at room temperature The reaction mixture was filtered and the filter cake washed 10 with absolute ethanol (100 ml) The filtrate was concentrated in vacuo to afford an oil. Purification of the crude product by flash chromatography (silica, 0-2 5% methanol/dichloromethane), followed by recrystallization from ether/heptane afforded the title compound as a solid 15 (2 3 g) , m p 127-128°C Analysis. Calculated for C^H^N., • 74 62%C 5 30%H 20 08%N Found 74 21%C 5 33%H 20 11%N 20 EXAMPLE 72 n I NH N- (2-Pvridinvl) -lH-mdol-1-amine WO 97/04777 -78- PCT/US96/I1408 Potassium tert-butoxide (3,4 g) was added to a room temperature solution of N-aminoindole (2.0 g) m 1-methyl-2-pyrrolidmone (40 ml) . After stirring for one hour, 2-chloropyridine (1.6 ml) was added and the resulting 5 solution was stirred for forty-eight hours The reaction mixture was then quenched with water, diluted with ethyl acetate (250 ml) and washed with brine (3 x 250 ml) The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give an oil. Purification of the 10 residue by flash chromatography (silica, 0-5% ethyl acetate/dichloromethane) gave the title compound as a solid (2.0 g) , m p 109-110°C Analysis. Calculate Found 74 34%C 5.29%H 20 05%N 15 Calculated for C13HnN3: 74 62%C 5 30%H 20.08%N EXAMPLE 73 Ha 20 3-Methvl-l- (propyl-4-pvridinvlammo) -1H-mdol-5-ol hemi- oxalate 3-Methyl-5-(phenylmethoxy)-1-(propyl-4-pyridmylamino)-lH-mdole (7.8 g) m absolute ethanol (275 ml) was hydrogenated at 344 74 Kpa (Parr shaker, 50 psi) 25 over ten percent palladium on carbon (0 8 g) at 50°C for two to three hours. The catalyst was removed by filtration and the solids were washed with methanol The combined filtrate was concentrated and the product purified via WO 97/04777 -79- PCT/US96/11408 flash column chromatography (silica, 2%triethylamine/ether) affording the product as an oil. This oil was dissolved in absolute ethanol Thereafter one equivalent of oxalic acid which had been dissolved in absolute ethanol was added and the title compound, m.p. 235-237°C, precipitated from solution and was collected by filtration. 10 Analysis. Calculated for C17H„N30*0 .5C,Ha04. 66. 23 %C 6.19%H 12.88%N Found- 65 91%C 6.33%H 12.58%N EXAMPLE 74 3-Methvl-l- (4-pyridinvlamino) -lH-mdol-5-ol 15 3-Methyl-5-phenylmethoxy-l-(4-pyridmylammo) -lH-mdole (2 2 g) dissolved m absolute ethanol (80 ml) was hydrogenated at 344.74 Kpa (Parr shaker, 50 psi) over ten percent palladium on carbon (0.26 g) at 5 0°C for two hours. The catalyst was removed by filtration and the solids were 20 washed with methanol Concentration and recrystallization from methanol afforded the title compound as a solid (0 5 g), m p. 239-241°C (dec.) 25 Analysis: Calculated for Cl4H13N.,0 Found: 70 28%C 69.95%C 5.48%H 5 .46%H 17 56%N 17 41%N m WO 97/04777 -80- SXMPLE 75 PCT/US96/11408 10 15 1- rPropvl-4- (3-f luoropvridinvl )ammo1 -lH-indol-5-ol hydrochloride A solution of N-(3-fluoropyridm-4-yl)-5-phenylmethoxy-N-propyl-lH-indol-l-amine (15 0 g) m ethanol (200 ml) was hydrogenated at 344.74 Kpa (Parr shaker, 50 psi) over ten percent palladium on carbon (1.5 g) at 50°C for three hours. Upon cooling, the mixture was filtered, and the filtrate evaporated to a solid (11.4 g). This material was purified by preparative HPLC chromatography [silica, ethyl acetate/dichloromethane (1.3)]. The fractions containing product were evaporated to a solid (8.5 g). A portion (2,0 g) of this material was dissolved in ethanol (50 ml) The pH was adjusted to 1 with addition of ethereal hydrogen chloride and then diluted with ether (200 ml) The resulting precipitate was collected and dried to give the title compound (2.1 g), m p 218°C (dec ) 20 Analysis. Calculated for C16H16FN3OHCl Found• 59 .72%C 5 33%H 59 .30%C 5 36%H 13.06%N 12.62%N WO 97/04777 -81- PCT/US96/11408 1-r(3-Fluoro-4-pvridinvl)propylamino!-3-methvl-lH-indol-5- Ql 5 1-f (3-Fluoro-4-pyridmyl )propylammo]-3 -methyl-5- (phenylmethoxy)-lH-mdole (T 5 8 g) was dissolved in absolute ethanol (200 ml) and hydrogenated at 344.74 Kpa (Parr shaker, 50 psi) at 50°C for seven and one-half hours Thereafter, the mixture was filtered and the solids were 10 washed with absolute ethanol The combined filtrates were concentrated and the residue was purified via preparative HPLC (silica, 3 1 dichloromethane/ethyl acetate) to afford an oil (5 0 g) Addition of ethyl acetate solidified the product which was recrystallized from ethyl acetate to give 15 a solid, m p 157-160°C Analysis: Calculated for C^Ft^O 68.21%C 6 06%H 14 04%N Found: 67.81%C 6 09%H 13 73%N 20 EXAMPLE 77 N-(2. 5-Dimethvl-lH-Pvrrol-l-vl) -N- (n-propvl) -4 -pyridmamine maleate A solution of N-(2,5-Dimethyl-lH-pyrrol-l-yl)-4-25 pyridmamine (2 2 g) in dimethylformamide (20 ml) was slowly added to an ice-cooled suspension of sodium hydride (60% oil dispersion, 0.6 g washed with hexanes) m dimethylformamide (5 ml) After anion formation, a WO 97/04777 PCT/US96/11408 solution of 1-bromopropane (1.7 g) m dimethylformamide (5 ml) was added. After one hour the reaction mixture was quenched with ice-water and extracted with ethyl acetate. The organic extract was washed with water and brine, dried 5 over anhydrous magnesium sulfate, filtered and evaporated to yield an oil (2.7 g). This oil was purified by flash chromatography (silica, ethyl acetate) to give an oil (2.5 g). This oil was converted to the maleate salt in methanol-ether to give the crystalline title compound (3 0 10 g) , m.p. 133-135°C. Analysis. Calculated for C^H^N^C^O, Found 62.59%C 6.71%H 62.58%C 6.71%H 12.17%N 12 10%N </div>

Claims

<div class="application article clearfix printTableText" id="claims"> m -83- 3 12 5 7 7. i WHAT WE CLAIM IS.

1. Use of a compound for the preparation of a pharmaceutical composition for the treatment of convulsions wherein the compound has the formula (O)n 10 wherein R is hydrogen, (C1-C5)alkyl, (Co-Cg)alkenyl, (C2-C5)alkynyl or pnenyl (C^-Cg) alkyl, R- is hydrogen, nalogen or (C]_-Cg) alkyl, R2 is r.ydrogen, nalogen or (Ci_-Cg) alkyl, or 15 ?- and R- taken cogemer witn the carccns to vnicn tney are attacned fom a benzene ring fused to tne pyrrole ring therein the oenzer.e ring is optionally substituted oy one or two suostituencs independently selected fron the group of nalogen, 20 (Ci_-Cg) alkyl, (C^-Cg) alco-cy, aryl (O-Cg) alko cy, r./droxy, nitro, ammo, ((>-C51 al<ylam_nc or d_ ''C_-Cg) alkylamino, is hydrogen, nalogen cr (C>-Cg'al<yl, ?"= is nydrcgen, nalogen, aa.no or (C> -Cg>alk/1, n is 0 cr 1, or a pnarraceu:-c5l..' acceptable ac_d addit-on salt tr.ereof -84- 3 12 5 7 7. 2. Use of a compound according to claim 1 wherein the compound has the formula R2 -|-R3 R1*/Ss'N N I (O)n wherein R is hydrogen, (Ci_-Cg) alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl or phenyl (Cj_-Cg) alkyl, R- is hydrogen, halogen or (Ci_-C,5) alkyl, R- is hydrogen, halogen or (Ct_-C^ ) alkyl, r3 is hydrogen, halogen or (Ci_ -C5) alkyl, R^ is hydrogen, halogen, ammo or (Ci_-Cg) alkyl, and n is 0 or 1, or a charmaceuticallv accectaole acid addition salt tnereof 3 Use of a compound according to claim 2 vnerem R- anc are nydrcgen, ?~* is hydrogen or (C2.-C5) al<yl and n is 0 4 Use of a compound according cc cla_m 2 vr.ereir. tne compound has the formula -85- (X)rrrp | w 3 12 5 7 7." fv (0)n wherein R is hydrogen, (C^-Cg)alkyl, (C2~Cg)alkenyl, (C2-Cg)alkynyl or phenyl(Cj-Cg)alkyl, R3 is hydrogen, halogen, or (C^-Cg) alkyl; R4 is hydrogen, halogen, amino or (C^-Cg)alkyl; X is hydrogen, halogen, (Ch-Cg) alkyl, (C]_-Cg) alkoxy, aryl (Ci_-Cg) alkoxy, hydroxy, nitro, ammo, (Ci_-Cg)alkylamino or di (C^-Cg) alkylamino, m is 1 or 2, n is 0 or 1, and z is 1 or 2, or a pr.armaceutically acceptable acid addition salt tnereof 5 Use of a compound according to claim 4 wherein X is hydrogen, R^ is nydrcgen or metnyl, R^ is hydrogen or fluoro and n is 0 6 Use of a compound according to claim 2 wnerem the compound is namely 11- 1 1~-pyrrol-l-yl) -4-pyridmamine, M-netnyl-N- (lH-pyrrol-l-yl) -4-p/ndmamme, N-etnyl-N- (IH-pyrrcl-l-yi) -4-pvridmamme, M-prcpyl-M- (lH-pyrrol-l-yl) -4 -pyridmamine, M-pner./ltietnyl-M- (lH-pyrrol-l-yl) -4-pyridmarrme, N- (but/l) -N- (lH-pyrrol-l-yl) -4-pyridmamine, -86- k 3 12577, 9 N- (2-propenyl) -N- (IH-pyrrol-l-yl) -4-pyridmamine, N- (2-propynyl) -N- (lK-pyrrol-l-yT ) -4-pyridmamine, N- (2-chloro-lH-pyrrol-l-yl) -N-methyl-4-pyridmamine, N- (2-chloro-lH-pyrrol-l-yl)-N-ethyl-4-pyridmamine, 5 N- (2-chloro-lH-pyrrol-l-yl)-N-propyl-4-pyridmamine, N- (2-chloro-lH-pyrrol-l-yl) -4-pyridmamine,

2-butyl-N-methyl-N-(IH-pyrrol-l-yl)-4-pyridmamine, N-(2-ethyl-lH-pyrrol-l-yl)-N-methyl-4-pyridmamine, N-methyl-N-(2-propyl-lH-pyrrol-l-yl)-4-pyridmamine, 10 N- (4-pyridmyl) - lH-indol-l-amme, N-methyl-N- (4-pyridmyl) -lH-mdol-l-amme, N-ethyl-N- (4-pyridmyl) -lK-indol-l-amme, N-propyl-N- (4-pyridmyl) -lK-mdol-l-amme, 5-methoxy-N-propyl-N- (4-pyridmyl) -IH-mdol-l-amme, 15 3-ethenyl-N-methyl-N- (4-pvridmyl) -IH-mdol-l-amine, 3-echyl-N-metnyl-N- (4-pyridmyl) -IH-mdol-l-amme, 5-chloro-N- (4-pyridmyl) -IH-mdol-1 -amine, 5 -cnloro-N-propyl-N- (4 -pyridmyl) - IH- mdo 1-1 -amine, 5-bromo-M- (4-pyridmyl) -IH-mdol-l-amme, 20 5-bromo-N-methyl-N- (4-pyridmyl) -IH-mdol-l-amme, 5-bromo-N-propyl-N- (4-pyridmyl) -lH-mdol-l-amme, 5-nitro-N- (4-pyridmyl) -lH-indol-l-amine, N-mecnyl-5-nitro-N- (4-pyridmyl) -IH-mdol-l-amme, 3-met.iyl-N- (4-pyridmyl) - IH - mdo 1 -1 - amine, 25 3 -met.iyl-N-propyl-M- (4-pyridmyl) -^H-mdol-1 -amine, N- (2- fluoro-4-pyridmyl) -3-metr.y 1 -IH-mdol-l-amme, N- (3-fluoro-4-pyndmyl) -M-propyl-3 -methyl-lH-mdol-l-amine, N- (3 - fluoro-4-pyridmyl) -M-proc/1 -IH-mdol -1 -amme, 30 2-netr.yl-N- (4-pyridmyl) -Irl-mdcl-l-amme, N- (3 -metn/1- 4 -pyridm/1) -1-- mcc 1-1 -amine, N- (3 -rne-nyl-4-pyric_n/l) -I'l-prcp^ 1- IH-mdol-1 -amme, M- (3 -f luoro-4 -pyrid.rw l-l.-I-mdc 1 -1 -anme, N- (3 -cnloro-4-pi/ridm,/1) -I-i-mdcl-i-anme, 25 N- (2 - ( f luoro-4-ovr_ain"/l) -2-Tietr. /1-lH-mdol-i-amme, ' i U.. I . , 0, 111 JU.J i£39 R L' c civn 3 1 2 5 7 7.1 N- (3-chloro-4-pyridmyl)-3-methyl- M-propyl-N-(4-pyridmyl)-3-ethenyl-lH-indol-l-amine, 3-ethyl-N-propyl-N- (4-pvridmyl) -IH-mdol-l-amme, N-butyl-N- (4-pyridmyl-lH-mdol-l-amme, N- (2-propynyl) -N- (4-pyridmyl) -IH-mdol-l-amme, N- (2-methylpropvl) -N- (4-pvridmyl) -IH-mdol-l-amme, N-pentyl-N- (4-pyridmyl) -IH-mdol-l-amme, N- (1-methylpropvl) -M- (4-pyridmyl) -lK-mdol-l-amme, N- (1-methylethyl) -N- (4-pyridmyl) -IH-mdol-l-amme, 2 -me thyl -N-propyl -N- (4 -pyridmyl) - IH- mdol -1 - amme, N- (3-fluoro-4-pyridmyl) -N- (2-propenyl) -3-methyl-IH-mdol 1-amine, N- (3-chloro-4-pyridmyl) -N-propyl-lH-mdol-l-amme, N- (3-fluoro-4-pyridmyl) -N- (2-propynyl) -IH-mcol-l-amme, N- (3-fluoro-4-pyridmyl) -3-methyl-N- (2-propynyl) -IH-mdol 1-amine, N- (3-fluoro-4-pyricmyl) -2-methyl-N-propyl-lH-mdol-1-arame, N- (3-chloro-4-pvridmyl) -3-metnyl-N-propyl-lH-mdol-l-anme, N- (3-fluoro-4-pyridmyl) -N- (2-propenyl) -IH-mcol-l-amme, 4- [N- (IH-mdol-l-yl) ] -3 , 4-pyridmamine, 3-chloro-N- (4-pyridmyl) -IH-mdol-l-amme, 3-cnloro-N-propyl-N- (4-pyridmyl) -IH-mdol-l-amme, 3-ethyl-N-metnyl-N- (4-pyridmyl) -IH-mcol-l-amme, 1- [propyl-4- (3 - fluoropy ridmyl) ammo ] -lH-mcol-5-ol, 3-netnyl-l- (4-pyridmylammo) -lH-mdol-5-ol, 3 -me t.iy 1 -1 - (propyl -4 -pyr idir.yla.ni.no) - IH - mdo 1 - 5 -c 1, 1- [ (3 -f luoro-4-pyndm_/l) propylammoj -3 -netnyl-lH-mdcl-5-ol, N- (3 -cr.loro-4-pyr id_r.y_) -3 - "ethyl -IH -ir.dol -1 -anir.e, M- (3-pyncir.yl) -ll--ir.dc 1 - 1-a.n.r.e , M- (2-pyndir./l) -Ih-mdcl-l-ar-ne, M- (2 , 5-dmecn/--lH-pvrrcl-l-j/1) -M- (r.-pr-p./1) -4-pyncmamme, or u _ v, ) t', I JUfJ 1£39 R E C E | v P n -88- 3 12 5 7 7. 1

3-fluoro-N-propyl-M-(lH-pyrrol-l-yl)-

4-pyridinamine 7. Use of a compound according to claim 5 wherein the compound is namely 5 3 -aminomethyl-N-propyl-N- (4-pyridmyl)-IH-mdol-1-amine, or 3 -ammoethyl-N- (4-pyridinyl) -lH-mdol-l-amine 8. Use of a compound as defined in Claim 1 for the preparation of a pharmaceutical composition for the treatment of convulsions substantially as herein described with reference to any example thereof. .*ioecM3r MARION eousseu By the authorised agents A J PaiK & Son -*• Jl'.'J >^3 R r r i v r n </div>